KR20230028244A - Cyclic deuterated gaboxadol and its use for the treatment of mental disorders - Google Patents

Abstract

Cyclic deuterated gaboxadol is provided. Cyclic deuterated gaboxadol is useful in the treatment of psychiatric disorders and is more effective than non-deuterated gaboxadol in such treatment. Deuterated gaboxadol is useful in combination with other compounds to provide additive and synergistic effects in patient treatment. In certain embodiments, the deuterated gaboxadol is d6-gaboxadol.

Description

Cyclic deuterated gaboxadol and its use for the treatment of mental disorders

CROSS REFERENCES TO RELATED APPLICATIONS

This application is based on U.S. Provisional Patent Application No. 63/027,923 filed on May 20, 2020, U.S. Provisional Patent Application No. 63/027,953 filed on May 20, 2020, U.S. Provisional Patent Application No. Patent Application No. 63/028,457 claims the benefit of US Provisional Patent Application No. 63/028,472, filed on May 21, 2020, each of which is incorporated herein by reference in its entirety.

field of invention

The present invention is directed to treating mental disorders by using an effective amount of deuterated gaboxadol or a pharmaceutically acceptable salt thereof alone or in combination with other drugs such as ketamine and/or lithium in a subject in need of treatment for a mental disorder. It relates to methods and compositions for the treatment of deuterated gaboxadol, synthesis of deuterated gaboxadol and to compositions comprising deuterated gaboxadol for the manufacture of medicaments useful in therapy.

According to the World Health Organization (WHO), depression is a leading cause of disability and disease, affecting more than 300 million people worldwide and costing the world economy an estimated $1 trillion in lost productivity each year. The Centers for Disease Control (CDC) estimates that in the United States alone, 20 to 25 percent of all adults ages 18 and older and 10.9 percent of young adults ages 18 to 25 experience at least one episode of major depression each year. Mental illnesses such as major depression, left untreated, are the leading cause of suicide in the United States, claiming more than 47,000 American lives each year, or one person dying by suicide every 11 minutes (Shepard et al., Suicide Life Threat Behav. (2016) 46(3):352-62.). There is one suicide for every 25 suicide attempts, which means that there are about 250,000 people who become suicide survivors each year. Thus, there is a significant unmet need for agents for the treatment of psychiatric disorders such as suicidal ideation and treatment-resistant depression (TRD).

Mental disorders are common worldwide and in the United States, with nearly 1 in 5 adults in the United States estimated to experience a mental illness (>50 million in 2019), with the highest prevalence of mental illness in women and young adults aged 18-25, which is ( In alphabetical order) agoraphobia, anorexia nervosa, any anxiety disorder, attention deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), binge eating disorder, bipolar disorder, borderline personality disorder, bulimia nervosa, dementia, eating disorder, generalized anxiety disorder, major depression, obsessive-compulsive disorder (OCD), panic disorder, persistent depressive disorder (dysthymic disorder), personality disorder, post-traumatic stress disorder (PTSD), postpartum depression, schizophrenia, social anxiety disorder, social and certain other phobias and treatment-resistant depression (TRD). It has been widely observed that psychopharmacological agents used to treat psychiatric disorders have only modest efficacy and significant side effects. There is therefore a significant unmet need for pharmaceuticals for the treatment of mental disorders.

Also called gaboxadolum or THIP (4,5,6,7-tetrahydroisoxazolo(5,4-c) pyridin-3-ol; C6H8N2O2; Cas No: 64603-91-4; PubChem CID: 3448) Gaboxadol is a selective GABA _A receptor agonist with a preference for the δ-subunit containing the GABA _A receptor. In the early 1980s, gaboxadol was used as a treatment for tardive dyskinesia, Huntington's disease, Alzheimer's disease (Mohr, Bruno et al. Clin Neuropharmacol. 1986; 9(3):257-63) and spasticity, as well as efficacy as an analgesic and anxiolytic. It was the subject of a series of pilot studies testing its efficacy. In the 1990s, gaboxadol entered late development for the treatment of insomnia. Development was discontinued after a 3-month efficacy study showed that the compound did not show significant effects on sleep initiation and sleep maintenance (ClinicalTrials.gov identifier: NCT00209963). Methods of treating depression with gaboxadol are disclosed in WO2004112786, which is incorporated herein by reference in its entirety.

A clinical trial was conducted to investigate the efficacy of gaboxadol in the symptomatic treatment of Angelman syndrome (a developmental disorder) (ClinicalTrials.gov identifier: NCT02996305) (Cogram, Deacon et al. 2019). Patent applications on related subject matter include US Patent No. 9,744,159, published US Patent Application No. 2017/348232, and WIPO International Patent Application WO2017015049, the contents of which are incorporated herein by reference in their entirety.

ClinicalTrials.gov Identifier: Clinical trial by Lundbeck reported under NCT00807248 treated 490 patients with daily oral doses of escitalopram (20 mg) and gaboxadol (5 mg or 10 mg) did Trials have confirmed that oral gaboxadol in this amount provides no additional benefit over escitalopram alone in the treatment of patients with severe major depressive disorder. A report on this trial is found in Kasper et al (2012) Int J Neuropsychopharmacol. 2012 Jul;15(6):715-25]. The trial did not test the effect of gaboxadol alone.

Gaboxadol (4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridin-3-ol) (THIP) is also described in EP Patent Nos. 0000338 EP 0840601, EP1641456, US Patent Nos. 4,278,676, 4,362,731, 4,353,910 and WO 2005/094820, the contents of which are incorporated herein by reference in their entirety.

The effect of deuteration is reviewed by Harbeson and Tung, 2014; Perrin and Dong, 2007; Perrin et al., 2005; Turowski et al., 2003]. Binding isotope effects can positively or negatively contribute to the measured deuterium kinetic isotope effect (DIE) (Schramm, 2007; Schwartz and Schramm, 2009). These DIE changes are primarily due to the increased energy required to break carbon-deuterium (C–D) covalent bonds over the energy required to break carbon–hydrogen (C–H) bonds. The major DIE can be expressed as kH/kD, the ratio of C-H to C-D bond-cleavage (Harbeson and Tung, 2014). The DIE effect can be expected, for example, in drug metabolism by cytochrome P450 (CYP) (Meunier et al., 2004). Gaboxadol is not metabolized by CYP, and most of the drug (84-93%) is excreted unchanged in the urine in the form of unmetabolized drug and glucuronic acid conjugates (Schultz et al., 1981).

Citation of any reference herein, including publications, patents and patent applications, is not to be construed as an admission that such reference is prior art to the present invention.

Treating a mental disorder by administering a compound to a patient in need thereof requires a useful compound to elicit a favorable response from the patient. The use of deuterated gaboxadol addresses this need by providing a compound that elicits a higher response in the brain of a patient compared to non-deuterated gaboxadol. Deuterated gaboxadol can be administered to a patient along with an additional compound to provide an additive or synergistic response in the patient.

The present invention provides gaboxadol with a deuterium present at the ring carbon position of the tetrahydro-pyridine ring of the molecule. Cyclic carbon deuterated d2-gaboxadol 7,7 and d6-gaboxadol were more potent in specific brain regions of interest than equivalent doses of non-deuterated gaboxadol, as measured by whole-brain activation studies in mice. It has been shown herein to induce high levels of brain activation, thus suggesting, for the first time, that cyclic carbon deuterated gaboxadol may be an excellent agent for the treatment of psychiatric disorders.

As shown in the examples, the present disclosure demonstrates that administration of deuterated gaboxadol is more effective than equivalent doses of gaboxadol, with some key differences presumed to be related to the better safety profile of gaboxadol. It is a pharmacologically effective treatment and is described as producing a broad brain activation pattern very similar to ketamine at lower doses than gaboxadol.

In addition, as shown in the Examples below, brain imaging of mice also shows additive and synergistic effects between gaboxadol and ketamine, indicating that even though the drugs act on very different molecular targets, their downstream effects are , suggesting that it leads to shared brain circuit-based mechanisms.

For purposes of the description herein, the terms "ring carbon deuterated gaboxadol" and "deuterated gaboxadol" and "deuterated gaboxadol compounds" refer to those whose abundance exceeds the naturally occurring deuterium abundance. Enriched with deuterium (i.e., deuterium occurs in place of hydrogen in all molecules in nature at about 0.0156%, the natural abundance of deuterium), at one or more ring carbon positions of the tetrahydro-pyridine ring of gaboxadol. are used interchangeably to refer to forms of gaboxadol that have deuterium atoms at (i.e., positions 4, 5 and 7). Individual forms of deuterated gaboxadol, including forms having 1 to 6 deuterium atoms, are described below. In certain embodiments, a ring carbon deuterated gaboxadol of the present invention is combined with a ring carbon of a tetrahydro-pyridine ring of gaboxadol using, for example, any of the methods provided herein or processes known in the art. It is synthesized to incorporate deuterium at one or more of the six relevant hydrogen positions.

In one aspect, the present invention provides a method of treating a mental disorder by administering to a patient in need thereof a pharmaceutical composition comprising a therapeutically effective amount of deuterated gaboxadol or a pharmaceutically acceptable salt thereof. provided, which in certain embodiments is administered from about 1 mg to about 300 mg of deuterated gaboxadol or a pharmaceutically acceptable salt thereof.

Embodiments of the therapeutic aspects of the present invention include methods of treatment comprising administering deuterated gaboxadol. As used herein, treatment and therapy may be interchangeable. The course of therapy may include a first administration of deuterated gaboxadol and additional administrations or multiple additional administrations of deuterated gaboxadol. As used herein, in a course of therapy of this kind, the initial administration may be referred to as the preceding administration and the further administration(s) may be referred to as the subsequent administration(s). As used herein, “first administration” or “initial administration” or “prior administration” may be used interchangeably and may also be referred to as “prior administration” when subsequent administrations are contemplated. “Additional administration” or “subsequent administration” may be used interchangeably herein.

Certain embodiments of the present invention provide methods of treating (in certain embodiments, reducing the risk of suicide and/or treating depression, eg, achieving rapid relief of depression or one or more symptoms of depression) of a mental disorder, the methods is sufficient to treat a mental disorder (eg, by achieving relief of one or more symptoms of depression), reduce the risk of suicide, and/or treat depression, deuterated gaboxadol or a pharmaceutical composition thereof; and administering an effective amount of the acceptable salt to a subject in need of treatment for a mental disorder. The deuterated gaboxadol of the present invention may be administered alone or in combination with other drugs.

Certain embodiments of the present invention provide methods of treating (in certain embodiments, reducing the risk of suicide and/or treating depression, eg, achieving rapid relief of depression or one or more symptoms of depression) of a mental disorder, the methods For patients in need of treatment for mental disorders, deuterated gaboxadol or a pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg to about 300 mg, preferably 1 mg to about 200 mg, more preferably 50 mg to 100 mg as a single dose treatment, wherein the treatment provides an improvement in the patient within 1 day.

In certain embodiments, the method of treatment is for achieving rapid onset or rapid relief of a therapeutic effect of one or more symptoms of a mental disorder, e.g., a psychiatric disorder, wherein the rapid relief, rapid relief, or rapid onset of a therapeutic effect is debilitating. The onset or amelioration of a therapeutic effect within 24 hours or 12 hours or 6 hours or 2 hours after administration of digestive gaboxadol to a patient.

In certain embodiments, the method of treatment comprises performing an initial administration of deuterated gaboxadol or a pharmaceutically acceptable salt thereof, and optionally further administration(s) of deuterated gaboxadol, wherein further subsequent administrations include: within about 12 hours of the preceding, initial administration, preferably within about 6 hours, and most preferably within about 180 minutes of the initial administration. An optional second administration, sometimes referred to as a subsequent administration, may be administered if the patient's clinical tests demonstrate an insufficient response within 160 minutes immediately following the first administration. In one embodiment, the insufficient response is an increase in EEG power density of less than 30% at about 160 minutes after the first administration. EEG power density is preferably calculated in the range of 4.75-8.0 Hz. Alternatively, an insufficient response may be a whole-head MEG planar gradiometer increase of less than +3 in combined delta, theta and alpha activity at about 160 minutes after first administration. Additional doses include up to the remainder of the maximum total first dose of 200 - 300 mg of deuterated gaboxadol. An insufficient response may also mean not achieving a certain blood level of gaboxadol.

In certain embodiments, the method of treatment comprises performing an initial administration of deuterated gaboxadol, or a pharmaceutically acceptable salt thereof, and, optionally, if an insufficient response is identified, approximately immediately after the initial administration of deuterated gaboxadol. and performing additional administration(s) of non-deuterated gaboxadol or a pharmaceutically acceptable salt thereof within 12 hours, preferably within about 6 hours, and most preferably within about 180 minutes of the initial administration. .

In certain embodiments, the method of treatment comprises performing an initial administration of gaboxadol or a pharmaceutically acceptable salt thereof, and optionally, if an insufficient response is identified, resuscitation within about 12 hours immediately following the initial administration of gaboxadol. and conducting additional administration(s) of digested gaboxadol or a pharmaceutically acceptable salt thereof.

In certain embodiments, imminent risk of suicide in a patient suffering from acute suicidal tendencies comprising administering to the patient a single dose of 10 to 200 mg of deuterated gaboxadol or a pharmaceutically acceptable salt thereof. Methods are provided for reducing the incidence of suicidal ideation, optionally wherein the dosage reduces the occurrence of suicidal ideation within about 24 hours of administration.

In certain embodiments, a method of treating a mental disorder, eg, reducing the risk of suicide or achieving rapid relief from depression, is provided, the method comprising deuterated gaboxadol or a pharmaceutically acceptable product thereof. A first pharmaceutical composition comprising a salt and a second pharmaceutical composition comprising ketamine, SAGE-217, tiagabine, clozapine and/or gaboxadol and pharmaceutically acceptable salts thereof are administered to a patient in need of treatment of a mental disorder. and administering to the patient. The second pharmaceutical composition may be administered concurrently, contemporaneously or sequentially.

In certain embodiments, deuterated gaboxadol and ketamine are each provided in synergistic dosages and may be administered synchronously, simultaneously or sequentially, in the same or separate pharmaceutical compositions.

A particular embodiment of the present invention is a therapy for reducing the risk of suicide and/or treating depression, eg, achieving rapid relief of depression or one or more symptoms of depression, which is deuterated gaboxadol or a pharmaceutically acceptable form thereof. performing the first administration of the salt to a subject in need thereof in an amount sufficient to reduce the risk of suicide and/or treat depression, eg, rapidly relieve depressive symptoms, and optionally deuterated gastric radiation Additional administration(s) of stone or a pharmaceutically acceptable salt thereof are performed within less than about 6 hours immediately after the first administration, and if the patient experiences a risk of suicide and/or recurrence of depressive symptoms, additional administration Including performing (s).

In certain embodiments, the first administration comprises administration of gaboxadol or a pharmaceutically acceptable salt thereof and the further administration(s) comprises administration of deuterated gaboxadol or a pharmaceutically acceptable salt thereof.

In certain embodiments, the first administration comprises administration of deuterated gaboxadol or a pharmaceutically acceptable salt thereof and the further administration(s) comprises administration of gaboxadol or a pharmaceutically acceptable salt thereof.

In certain embodiments, one or more additional administrations are given 1, 2, 3, 4, 5, 6, or 7 days after the first administration.

In certain embodiments, an optional second or additional administration is performed if the patient's neurological tests demonstrate an insufficient response within about 180 minutes immediately after the first administration.

In certain embodiments, an insufficient response is an increase in electroencephalogram (EEG) power density of less than 30% relative to baseline within about 180 minutes after the first administration, or combined delta, theta, and alpha activity within about 180 minutes after the first administration. Whole head magnetoencephalography (MEG) planar durometer increase of less than +3 in .

In certain embodiments, the electroencephalogram (EEG) power density is calculated in the range of 0.25-8.0 Hz or in the range of 4.75-8.0 Hz.

In certain embodiments, the electroencephalogram (EEG) power density is sigma (11.5-15.0 Hz), beta-1 (15.5-20.0 Hz), beta-2 (20.5-25.0 Hz), or beta-3 (25.5-32.0 Hz). Calculated in range.

In certain embodiments, the optional second or additional administration(s) of deuterated gaboxadol, gaboxadol, or a pharmaceutically acceptable salt thereof, results in a neurologic test of the patient immediately after the first administration by about 30, about 60, about It is performed if an insufficient response is demonstrated within 90 or about 120 minutes.

In certain embodiments, an insufficient response is an increase in electroencephalogram (EEG) power density of less than 30% relative to baseline within about 180 minutes after the first administration, or about 30, about 60, about 90, or about 120 minutes after the first administration. Whole head magnetoencephalography (MEG) planar durometer increase of less than +3 in combined delta, theta, and alpha activity within

In certain embodiments, the method provides amelioration of at least one symptom of suicide risk, wherein the symptom includes, but is not limited to, suicidal ideation, acute suicidal tendencies, recurrent thoughts of death, suicidal behavior(s), suicide attempt(s), risk of self-harm, and/or treatment-resistant depression.

In certain embodiments, the patient has not previously been treated with, is not currently being treated with, or does not respond to an anti-depressive treatment.

In certain embodiments, the first and/or additional administration comprises from about 1 mg to about 300 mg, preferably from about 1 mg to about 200 mg of deuterated gaboxadol or a pharmaceutically acceptable salt thereof.

In certain embodiments, the first and/or additional administration comprises from about 1 mg to about 300 mg of deuterated gaboxadol or a pharmaceutically acceptable salt thereof.

In certain embodiments, the first and/or additional administration comprises about 1 mg to about 20 mg of deuterated gaboxadol or a pharmaceutically acceptable salt thereof.

In certain embodiments, the first and/or additional administration comprises about 5 mg to about 10 mg of deuterated gaboxadol or a pharmaceutically acceptable salt thereof.

In certain embodiments, the first and/or additional administration comprises about 50 mg, 75 mg or 100 mg of deuterated gaboxadol or a pharmaceutically acceptable salt thereof.

In certain embodiments, the first and/or additional administration is an oral dosage form. In certain embodiments, the oral dosage form is an orally disintegrating form.

In certain embodiments, the first and/or further administration is intranasal.

In certain embodiments, the plasma T _max of deuterated gaboxadol is achieved within 45 minutes after the first administration.

In certain embodiments, the method comprises administering to the patient, before, after, or concurrently with the first administration, lithium, ketamine, AXS-05 (a fixed combination of dextromethorphan and bupropion), SAGE-217, allopregnanolone, Ganaxolone, alphadolone, alpaxolone, hydroxydione, minaxolone, pregnanolone, lenolone, AV-101 (L-4-chlorokynurenine), rapastinel (GLYX-13), MGS0039, LY-341,495 , MK-801 (dizocilpine), Ro 25-6981, lislenemdaz (CERC-301, MK-0657), afimostinel (NRX-1074), ranisemin (AZD6765), traxoprodil (CP- 101606), (2R,6R)-hydroxynorketamine, deagglomerating agent (INN) (RG1578, RO4995819), memantine, tiagabine, clozapine and [2-amino-4-(2,4,6-trimethylbenzylamino) )-phenyl]-carbamic acid ethyl ester (AA29504), and any one of the pharmaceutically acceptable salts of any of the foregoing.

In certain embodiments, the regimen comprises administering a dose of deuterated gaboxadol or a pharmaceutically acceptable salt thereof in combination with a dose of a second pharmaceutical agent, wherein deuterated gaboxadol or a pharmaceutically acceptable salt thereof The dosage of the pharmaceutically acceptable salt is up to about 20 mg, and the effect of the combination is additive or synergistic with respect to the individual administration of the agents rather than the combination.

In certain embodiments, the regimen comprises concurrently administering a synergistic dose of deuterated gaboxadol or a pharmaceutically acceptable salt thereof together with a synergistic dose of ketamine, wherein deuterated gaboxadol or A synergistic dose of a pharmaceutically acceptable salt thereof is about 20 mg or less, and a synergistic dose of ketamine is about 10 mg or less.

In certain embodiments, the synergistic dosage of deuterated gaboxadol or a pharmaceutically acceptable salt thereof is about 20 mg, about 19 mg, about 18 mg, about 17 mg, about 16 mg, about 15 mg, about 14 mg. mg, about 13 mg, about 12 mg, about 11 mg, about 10 mg, about 9 mg, about 8 mg, about 7 mg, about 6 mg, about 5 mg, about 4 mg, about 3 mg, about 2 mg, about less than 1 mg.

In certain embodiments, the synergistic dosage of ketamine is about 10 mg, about 9 mg, about 8 mg, about 7 mg, about 6 mg, about 5 mg, about 4 mg, about 3 mg, about 2 mg, about 1 mg or less than about 1 mg.

In certain embodiments, deuterated gaboxadol alone for the manufacture of a medicament for the treatment of a psychiatric disorder, including but not limited to reducing the risk of suicide in a patient at risk of suicide, treatment-resistant depression and/or rapid relief of depressive symptoms. The use of is provided herein.

Aspects of the present invention include methods and compositions wherein deuterated gaboxadol can synergistically act with lithium to enhance the action of lithium on brain signaling activity. In particular, the combination of deuterated gaboxadol with lithium (e.g., <600 mg per day) in substandard dosage ranges is associated with psychiatric disorders such as (both acute mania and long-term maintenance) bipolar disorder, depression, treatment resistance. It is believed to reduce the amount of lithium needed to treat depression and potentially suicidal tendencies in the absence of these side effects, particularly chronic side effects such as nephrotoxicity and chronic kidney disease. Thus, co-administration of deuterated gaboxadol with substandard doses of lithium is expected to lower the risk of side effects and facilitate the management of bipolar disorder and other psychiatric disorders that respond to lithium treatment. In addition, the standard dosage range of lithium (e.g., 600 mg to 1800 mg, with dosages up to 2400 mg per day) also synergizes with deuterated gaboxadol or, in certain embodiments, additionally It is believed that the addition of deuterated gaboxadol to the standard dose of lithium will prove useful in increasing the response to lithium in treatment-resistant patients who do not initially respond to conventional lithium monotherapy. suggests that it can

In one embodiment of the invention, the synergistic combination comprises deuterated gaboxadol and lithium, or a pharmaceutically acceptable salt of one or both of these compounds.

In certain embodiments, a synergistic combination in a pharmaceutical composition comprising another deuterated gaboxadol compound, such as lithium, or a pharmaceutically acceptable salt of one or both of these compounds, and a pharmaceutically acceptable carrier. provided herein.

In certain embodiments, a synergistic combination is a pharmaceutical composition comprising deuterated gaboxadol or a pharmaceutically acceptable salt and a second pharmaceutical composition comprising lithium or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier. provided herein.

In certain embodiments, when deuterated gaboxadol and lithium are given in combination, lithium, when administered daily to a subject in need thereof, is a standard of futility in treating bipolar disorder, depression, treatment-resistant depression, or suicidal tendencies. Provided in the following doses.

In certain embodiments, when deuterated gaboxadol and lithium are given in combination, the lithium, when administered daily to a subject in need thereof, is medically recommended for bipolar disorder, depression, treatment-resistant depression, or suicidal tendencies. It is given as a substandard dose that is below the dose.

In certain embodiments, when deuterated gaboxadol and lithium are given in combination, the lithium produces a substandard level of lithium that is ineffective for c-fos signaling in the brain of animal models as measured by Pharmacomapping. It is given in a dose that is an animal equivalent of the dose.

In preclinical testing, a substandard lithium human dose range is expressed by visualization of the induction of the immediate early gene (IEG) c-fos, eg in animals such as mice or rats, with lithium-induced brain activation. By mapping or recording lithium-induced changes in the animal's electroencephalogram (EEG), a standard dosage range can be distinguished and established.

In certain embodiments of this aspect, the substandard dosage of lithium is in the range of about 50 to about 600 mg lithium carbonate per day.

In certain embodiments of this aspect, the deuterated gaboxadol, when given to an animal, such as a mouse or rat, at an animal equivalent dose (AED), decreases the amount of c-fos activity in the brain as measured by pharmacomapping. Provided at human doses that do not induce induction, or that cause only low or moderate induction. In certain embodiments, low induction of c-fos activity in the brain occurs in 1 to 2 cortical regions, such as the anterior cingulate (ACA) and occipital lobe (RSP) cortices and/or 1 to 3 subcortical regions, such as the laminar nuclear demarcation. It is manifested by activation of the striatum (bed nuclei stria terminalis, BST), central amygdala (CEA), and auditory cortex (LC). In certain embodiments, moderate induction of c-fos activity in the brain occurs in three to six cortical regions, such as the ACA, RSP, gustatory (GU), instinctive (VISC), auditory (AUD), and visual (VIS) cortices and and/or by activation of four to six subcortical regions, such as the BST, CEA, LC, the nucleus of reunion (RE), the rhomboid nucleus (RH), and the medial central nucleus (CM) of the thalamus.

In certain embodiments of this aspect, the dosage of deuterated gaboxadol administered is from about 1 to about 15 mg, from about 15 to about 30 mg, or from about 30 to about 30 mg of deuterated gaboxadol per day for an adult human. in the 300 mg range.

In certain embodiments of this aspect, the lithium is provided as a standard dose of lithium.

In certain embodiments of this aspect, the standard dosage range for lithium is in the range of about 600 to about 1800 mg of lithium carbonate per day for an adult human, with a maximum dosage of 2400 mg per day.

In certain embodiments of this aspect, the deuterated gaboxadol is given at a dose that results in strong induction of c-fos activity in the brain when given to an animal, such as a mouse or rat, at an animal equivalent dose (AED). do. In certain embodiments, strong induction of c-fos activity in the brain occurs in more than six cortical regions, such as ACA, RSP, GU, VISC, AUD, VIS, motor (MO), agranular insular, AI), limbic (SS), prelimbic (PL) and lower part of the limbic system (ILA), parietal (PTL), temporal union (TEa), ectorhinal (ECT), internal olfactory (ENT), periolfactory (PERI), and piriform (PIR) cortex and foregut (claustrum (CLA)) and/or more than six subcortical regions such as BST, CEA, LC, RE, RH, CM, hippocampal CA1 region, cortical amygdala ( COA), basolateral and basolateral amygdala (BLA and BMA), medial amygdala (MEA), thalamic ventral posteromedial nucleus (VPM), subparafascicular nucleus (SPF), medial geniculate complex (MG) ), suprageniculate nucleus (SGN), paraventricular nucleus hypothalamic nucleus (PVH), hypothalamic posteromedial nucleus (DMH), tuberomammillary nucleus (TM), hypothalamic parathalamic nucleus (PSTN) and It is manifested by activation of the hypothalamic nucleus (STN), subthalamic nucleus, and nucleus to isolates (NTS).

In certain embodiments of this aspect, the amount of lithium and deuterated gaboxadol administered daily to a subject in need thereof is motor (MO), gustatory (GU), instinctive (VISC), agranular Lateral and inferior cortex (AI), auditory (SS), auditory, visual (VIS), auditory (AUD), prelimbic (PL) and infralimbic (ILA), occipital lobe (RSP), body parietal (PTL), temporal association ( TEa), external olfactory (ECT), internal olfactory (ENT), periolfactory (PERI), cutaneous (PIR), and anterior cingulate (ACA) cortices, and a cortical brain of a subject selected from the group consisting of the foregut (CLA) is synergistically effective in inducing IEG c-fos signaling in at least one region of.

In certain embodiments of this aspect, the amount of lithium and deuterated gaboxadol administered daily to a subject in need thereof is motor (MO), gustatory (GU), instinctive (VISC), agranular Lateral and inferior cortex (AI), auditory (SS), auditory, visual (VIS), auditory (AUD), prelimbic (PL) and infralimbic (ILA), occipital lobe (RSP), body parietal (PTL), temporal association ( TEa), external olfactory (ECT), internal olfactory (ENT), periolfactory (PERI), cutaneous (PIR), and anterior cingulate (ACA) cortices, and a cortical brain of a subject selected from the group consisting of the foregut (CLA) It is synergistically effective in inducing IEG c-fos signaling in at least two regions of the .

In certain embodiments of this aspect, the amount of lithium and deuterated gaboxadol administered daily to a subject in need thereof is motor (MO), gustatory (GU), instinctive (VISC), agranular Lateral and inferior cortex (AI), auditory (SS), auditory, visual (VIS), auditory (AUD), prelimbic (PL) and infralimbic (ILA), occipital lobe (RSP), body parietal (PTL), temporal association ( TEa), external olfactory (ECT), internal olfactory (ENT), periolfactory (PERI), cutaneous (PIR), and anterior cingulate (ACA) cortices, and a cortical brain of a subject selected from the group consisting of the foregut (CLA) It is synergistically effective in inducing IEG c-fos signaling in at least three regions of the .

In certain embodiments of this aspect, the amount of lithium and deuterated gaboxadol administered daily to a subject in need thereof is administered in the CA1 region of the hippocampus, the striatum nuclear striatum (BST), the central amygdala (CEA) , cortical amygdala (COA), basolateral and basolateral amygdala (BLA and BMA), medial amygdala (MEA), thalamic ventromedial posteromedial nucleus (VPM), subparapasial nucleus (SPF), medial geniculate complex (MG), Anterior superior nucleus (SGN), nucleus of recombination (RE), rhomboid nucleus (RH), and medial central nucleus (CM) of the thalamus, paraventricular nucleus hypothalamic nucleus (PVH), posteromedial nucleus of the hypothalamus (DMH), At least a portion of the subcortical brain of a subject selected from the group consisting of the mammillary nucleus (TM), the parathalamic nucleus (PSTN) and the subthalamic nucleus (STN), the brachial nucleus, the nucleus fossa (LC), and the nucleus of the tract (NTS). It is synergistically effective in inducing IEG c-fos signaling in one region.

In certain embodiments of this aspect, the amount of lithium and deuterated gaboxadol administered daily to a subject in need thereof is administered in the CA1 region of the hippocampus, the striatum nuclear striatum (BST), the central amygdala (CEA) , cortical amygdala (COA), basolateral and basolateral amygdala (BLA and BMA), medial amygdala (MEA), thalamic ventromedial posteromedial nucleus (VPM), subparapasial nucleus (SPF), medial geniculate complex (MG), Anterior superior nucleus (SGN), nucleus of recombination (RE), rhomboid nucleus (RH), and medial central nucleus (CM) of the thalamus, paraventricular nucleus hypothalamic nucleus (PVH), posteromedial nucleus of the hypothalamus (DMH), At least a portion of the subcortical brain of a subject selected from the group consisting of the mammillary nucleus (TM), the parathalamic nucleus (PSTN) and the subthalamic nucleus (STN), the brachial nucleus, the nucleus fossa (LC), and the nucleus of the tract (NTS). It is synergistically effective in inducing IEG c-fos signaling in both regions.

In certain embodiments of this aspect, the amount of lithium and deuterated gaboxadol administered daily to a subject in need thereof is administered in the CA1 region of the hippocampus, the striatum nuclear striatum (BST), the central amygdala (CEA) , cortical amygdala (COA), basolateral and basolateral amygdala (BLA and BMA), medial amygdala (MEA), thalamic ventromedial posteromedial nucleus (VPM), subparapasial nucleus (SPF), medial geniculate complex (MG), Anterior superior nucleus (SGN), nucleus of recombination (RE), rhomboid nucleus (RH), and medial central nucleus (CM) of the thalamus, paraventricular nucleus hypothalamic nucleus (PVH), posteromedial nucleus of the hypothalamus (DMH), At least a portion of the subcortical brain of a subject selected from the group consisting of the mammillary nucleus (TM), the parathalamic nucleus (PSTN) and the subthalamic nucleus (STN), the brachial nucleus, the nucleus fossa (LC), and the nucleus of the tract (NTS). It is synergistically effective in inducing IEG c-fos signaling in three regions.

In certain embodiments of this aspect, the amount of deuterium gaboxadol another compound, such as lithium, when administered daily to a subject in need thereof, is reduced in a subject selected from the group consisting of bipolar disorder, depression, treatment-resistant depression, and suicidal tendencies. are synergistically effective in treating psychiatric disorders.

In certain embodiments of this aspect, treatment of the subject's mental disorder is effective to improve a score on at least one mental state assessment scale specific for bipolar disorder, depression, treatment-resistant depression, or suicidal tendencies.

In certain embodiments of this aspect, another deuterated gaboxadol compound, such as lithium, when administered to a subject diagnosed with depression, increases the subject's Montgomery-Asberg Depression Rating Scale (MADRS) score. synergistically effective in increasing

In certain embodiments of this aspect, the deuterated gaboxadol another compound, such as lithium, when administered to a subject in need thereof, induces at least one psychotic disorder specific for bipolar disorder, depression, treatment-resistant depression, or suicidal tendencies. It is synergistically effective in increasing scores on status assessment scales.

In certain embodiments of this aspect, the deuterated gaboxadol another compound, such as lithium, when administered to a subject in need thereof, induces at least two psychotic disorders specific for bipolar disorder, depression, treatment-resistant depression, or suicidal tendencies. It is synergistically effective in increasing scores on status assessment scales.

In certain embodiments of this aspect, the deuterated gaboxadol another compound, such as lithium, when administered to a subject in need thereof, induces at least three psychotic disorders specific for bipolar disorder, depression, treatment-resistant depression, or suicidal tendencies. It is synergistically effective in increasing scores on status assessment scales.

In certain embodiments of this aspect, the lithium is in an amount sufficient to maintain a serum level of lithium in the range of about 0.2 to about 1.2 mmol/L when administered daily to a subject in need thereof.

In certain embodiments of this aspect, the lithium, when administered daily to a subject in need thereof, is in an amount sufficient to maintain a serum level of lithium in the subject in the range of about 0.4 to about 0.8 mmol/L.

In another aspect of the present invention, a pharmaceutical composition comprising any one of the foregoing embodiments of a synergistic combination of lithium and deuterated gaboxadol is disclosed.

In certain embodiments of this aspect, the pharmaceutical composition is in the form of a single tablet for oral consumption.

In certain embodiments of this aspect, the pharmaceutical composition is in the form of a controlled release dosage form.

In certain embodiments of this aspect, the pharmaceutical composition is in the form of an oral dosage form.

In certain embodiments of this aspect, the pharmaceutical composition further comprises one or more inert pharmaceutically acceptable excipients.

In certain embodiments of this aspect, the pharmaceutical composition is in the form of a single dosage unit having separate compartments for the lithium and the deuterated gaboxadol or pharmaceutically acceptable salts of one or both compounds thereof.

In another aspect, a kit comprising any of the foregoing pharmaceutical compositions is disclosed.

In another aspect, a method for treating a subject in need thereof comprising administering any one of the previous embodiments of a synergistic combination of lithium and deuterated gaboxadol is disclosed.

In certain embodiments of this aspect, the subject has been diagnosed with a mental disorder.

In certain embodiments of this aspect, the mental disorder is selected from bipolar disorder, depression, treatment-resistant depression, or suicidal tendencies.

In certain embodiments of this aspect, the combination is useful for nephrotoxicity, renal diabetes insipidus, chronic kidney disease, diarrhea, tremor, increased thirst, increased urination, vomiting, weight gain, poor memory, poor concentration, drowsiness, muscle weakness, hair loss, acne, and reducing at least one adverse side effect selected from the group consisting of hypothyroidism.

In certain embodiments of this aspect, the combination is useful for nephrotoxicity, renal diabetes insipidus, chronic kidney disease, diarrhea, tremor, increased thirst, increased urination, vomiting, weight gain, poor memory, poor concentration, drowsiness, muscle weakness, hair loss, acne, and reduction of at least two adverse side effects selected from the group consisting of hypothyroidism.

In certain embodiments of this aspect, the combination is useful for nephrotoxicity, renal diabetes insipidus, chronic kidney disease, diarrhea, tremor, increased thirst, increased urination, vomiting, weight gain, poor memory, poor concentration, drowsiness, muscle weakness, hair loss, acne, and reduction of at least three adverse side effects selected from the group consisting of hypothyroidism.

In another aspect, a method for treating a human diagnosed with bipolar disorder, depression, treatment-resistant depression, or acute suicidal tendencies is disclosed, the method comprising deuterated at a dose ranging from about 1 to about 300 mg/day. Capaxdol, lithium at a dose of about 50 mg to about 1800 mg lithium carbonate, with a maximum daily dose of 2400 mg [for a 60 kg human], or lithium carbonate, with a maximum dose of 40 mg/kg lithium at a dose of about 0.8 mg/kg to about 30 mg/kg; or in a synergistic combination, concurrently with lithium in an amount sufficient to achieve a lithium serum concentration of about 0.2 to 1.2 mmol/L; wherein the combination is administered at least once per day.

In another embodiment, a method for treating a human diagnosed with an acute form of bipolar disorder, depression, treatment-resistant depression, or suicidal tendencies comprises deuterated gaboxadol at a dosage ranging from about 1 mg to about 150 mg/day. , lithium at a dose of about 300 mg to about 1800 mg lithium carbonate/day [for a 60 kg human]; or in a synergistic combination, concurrently with an amount of lithium sufficient to achieve a lithium serum concentration of 0.4 to 1.2 mmol/L, wherein the combination is administered at least once per day.

In another embodiment, a method for treating a patient diagnosed with an acute form of bipolar disorder, depression, treatment-resistant depression, or suicidal tendencies comprises deuterated gaboxadol at a dose ranging from about 1 mg to about 150 mg/day. , lithium at a dose of about 50 mg to about 900 mg lithium carbonate [eg, for a 60 kg human]; or in a synergistic combination, concurrently with an amount of lithium sufficient to achieve a lithium serum concentration of 0.2 to 1.0 mmol/L, wherein the combination is administered at least once per day.

In another embodiment, a method for treating a patient diagnosed with an acute form of bipolar disorder, depression, treatment-resistant depression, or suicidal tendencies comprises deuterated gaboxadol at a dose ranging from about 1 mg to about 150 mg/day. , lithium at a dose of about 50 mg to about 900 mg lithium carbonate [eg, for a 60 kg human]; or with an amount of lithium sufficient to achieve a lithium serum concentration of 0.2 to 1.0 mmol/L, concurrently with additional combinations, wherein the combination is administered at least once per day.

In another embodiment, the use of deuterated gaboxadol and lithium in the manufacture of a fixed dose combination medicament is disclosed, wherein the lithium is in the range of about 10 mg to about 300 mg [optionally 50 mg to about 1800 in the form of mg]; Deuterated gaboxadol is present in the range of about 1 mg to about 150 mg for the treatment of human patients diagnosed with bipolar disorder, depression or acute suicidal tendencies.

In another embodiment, the use of a fixed dosage combination comprising lithium and deuterated gaboxadol in unit dosage form is disclosed, wherein the lithium is in the range of about 10 mg to about 360 mg [optionally in the range of 50 mg to 50 mg of lithium carbonate in the form of about 1800 mg]; Deuterated gaboxadol is present in the range of about 1 mg to about 150 mg for the treatment of human patients diagnosed with bipolar disorder, depression or acute suicidal tendencies.

In another embodiment, the use of a fixed dose combination comprising lithium and deuterated gaboxadol in unit dosage form is disclosed, wherein the deuterated gaboxadol is used in a human patient diagnosed with bipolar disorder, depression, or acute suicidal tendencies. For the treatment of deuterated gaboxadol present in the range of about 1 mg to about 150 mg and lithium in the range of about 40 mg to about 360 mg during the first week [optionally 200 mg to about 1800 mg of lithium carbonate in the form of], and after the first week the lithium is present in the range of about 10 mg to about 180 mg [optionally in the form of 50 mg to about 900 mg of lithium carbonate].

In another embodiment, the use of a synergistic combination of deuterated gaboxadol and lithium, or a pharmaceutically acceptable salt of one or both of these compounds, for reducing one or more symptoms of bipolar disorder, depression, or suicidal tendencies. use is disclosed.

In another embodiment, in the manufacture of a medicament for reducing one or more symptoms of bipolar disorder, depression or suicidal tendencies, deuterated gaboxadol and lithium, or a pharmaceutically acceptable salt of one or both of these compounds, are used. The use of synergistic combinations is disclosed.

One embodiment of the present invention is a deuterated gaboxadol having at least one deuterium present on a ring carbon of the tetrahydro-pyridine ring of gaboxadol.

One embodiment of the present invention is a ring carbon deuterated gaboxadol having a deuterium at the position of all six ring carbon hydrogens of the tetrahydro-pyridine ring of gaboxadol.

One embodiment of the present invention is a deuterated gaboxadol having deuterium at 5 of the 6 ring carbon hydrogen positions of the tetrahydro-pyridine ring of gaboxadol.

One embodiment of the present invention is a deuterated gaboxadol having deuterium at 3 of the 6 ring carbon hydrogen positions of the tetrahydro-pyridine ring of gaboxadol.

One embodiment of the present invention is a deuterated gaboxadol having deuterium at ring carbon hydrogen positions 5,5,7,7 of the tetrahydro-pyridine ring of gaboxadol.

One aspect of the present invention is a deuterated gaboxadol prepared by one of the synthetic schemes disclosed herein.

One aspect of the present invention relates to deuterated gaboxadol for the manufacture of a medicament for the treatment of a psychiatric disorder including, but not limited to, reducing the risk of suicide in a patient at risk of suicide, treatment-resistant depression and/or rapid-acting relief of depressive symptoms. is the use of

1A shows that the d1-gaboxadol form has six potential species.
Figure lb shows that the d2-gaboxadol form has 15 potential species.
Figure 1c shows that the d3-gaboxadol form has 20 potential species.
1D shows that the d4-gaboxadol form has 15 potential species.
Figure 1e shows that the d5-gaboxadol form has six potential species.
Figure 1f shows that the d6-gaboxadol form has only one species.
Figure 2 shows the form of deuterated gaboxadol and ring numbering system.
Figure 3 shows a schematic for the synthesis of 4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridin-7,7-d2-3-ol (d2-gaboxadol 7,7). show
Figure 4 shows the distribution of deuterated gaboxadol forms in the composition of Example 1B. According to calculations from raw data of peak intensity and abundance, 91% of the deuterated gaboxadol in the composition was in the form of d2-gaboxadol-7,7.
Figure 5 depicts exemplary synthetic routes for deuterated d2-gaboxadol 4,4 and d2-gaboxadol 5,5.
6 shows exemplary synthetic pathways for deuterated d4-gaboxadol 4,4,7,7, d4-gaboxadol 5,5,7,7 and d4-gaboxadol 4,4,5,5. show
Figure 7 depicts an exemplary synthetic route for deuterated d6-gaboxadol.
Figure 8 depicts an exemplary synthesis of d2-gaboxadol 7,7.
Figure 9 depicts an exemplary synthesis of d4-Gaboxadol 4,4,5,5.
10 depicts an exemplary synthesis of d6-Gaboxadol.
11 depicts an exemplary synthesis of d6-gaboxadol.
12 depicts an exemplary whole brain Pharmacomap showing drug-induced brain activation in mice. (A) Mice are treated with drug or vehicle solution for control using intraperitoneal (ip), oral (po), subcutaneous (sc), intramuscular (im) or intravenous (iv) delivery. (B) This leads to induction of the precursor gene c-fos in activated neurons, which typically peaks within 1.5 to 3 hours, depending on the pharmacokinetics of the drug. (C) Mice are killed after the corresponding period, c-fos induction is visualized using whole brain immunostaining, brains are chemically cleared (clear) and finally imaged by light-sheet fluorescence microscopy (LSFM). (D) Whole-brain scans are typically displayed as serial section datasets at an XYZ resolution of 4 x 4 x 5 microns. (E) c-fos+ cells are detected in these datasets using a custom training machine learning algorithm. (F) The whole-brain distribution of detected c-fos+ cells is displayed in 3D as a spatial map of centroid points in the 3D space of the mouse brain. (G) These 3D map distributions are spatially voxelized using 150-micron spherical voxels that are registered and overlapping in the reference mouse brain. (H) Finally, drug-induced pharmacomab is generated by statistical comparison of c-fos+ cell distribution of drug-treated and control vehicle-treated mice, typically using 6 animals per group.
Figure 13 depicts a pharmacomab-based comparison of d2-gaboxadol 7,7 at 6 mg/kg and gaboxadol at 6, 10 and 20 mg/kg. White indicates significant differences for A) d2-gaboxadol at 6 mg/kg, B) gaboxadol at 6 mg/kg, C) gaboxadol at 10 mg/kg and D) gaboxadol at 20 mg/kg. Indicates the spatial region of drug-induced activation. Regions with significantly stronger significant brain activation at d2-gaboxadol 6 mg/kg compared to gaboxadol 6 mg/kg pamacomab, highlighted with white dotted lines, include: medial orbital cortex ( ORBm), sublimbic cortex (ILA), dorsolateral and ventral anterior cingulate cortices (ACAd and ACAv), association cortical areas such as agranular lateral dorsal cortex (AI), gustatory cortex (GU), instinctive cortex (VISC) , the accessory olfactory nucleus (AON) and foregut (CLA), the rostral part of the lateral septum and the anterior part of the striatum (BSTa) and the subregion of the nucleus accumbens (ACB). The magnitude of d2-gaboxadol-induced brain activation in these regions was indeed comparable to non-deuterated gaboxadol at higher doses of 10 or even 20 mg/kg (Panels C and D). This comparison is further quantified in FIG. 15 .
Figure 14 depicts a pharmacomab-based comparison of d2-gaboxadol 7,7 at 6-30 mg/kg and gaboxadol at 6-50 mg/kg. White indicates spatial regions of significant drug-induced activation: top row: gaboxadol at 6, 10, 20, 30, 40 and 50 mg/kg; Bottom row: d2-gaboxadol at 6, 10, 20 and 30 mg/kg. Robust activation of the medial orbital cortex (ORBm) and accessory olfactory nucleus (AON) is observed with 10 and 20 mg/kg of gaboxadol as well as 6 mg/kg of d2-gaboxadol, but this response was not observed at 30 mg/kg. It is strongly reduced with d2-gaboxadol at doses greater than 10 mg/kg as well as with higher doses of gaboxadol. This comparison is further quantified in FIG. 19 .
FIG. 15 depicts quantification of pharmacomab-based comparisons of d2-gaboxadol 7,7 at 6 mg/kg and gaboxadol from 6 to 20 mg/kg in selected brain regions shown in FIG. 13 . The increase in c-fos+ cell numbers in drug-treated mice is expressed as a percentage of control saline-treated mice for each group: d2-gaboxadol at 6 mg/kg, gaboxadol at 6 mg/kg, 10 mg/kg gaboxadol and 20 mg/kg gaboxadol. Statistical differences between d2-gaboxadol at 6 mg/kg and gaboxadol at 6 mg/kg or 10 mg/kg are marked with an asterisk above the corresponding bar graph. Name abbreviations of the analyzed brain regions are listed above (see Figure 13 legend).
Figure 16 depicts a pharmacomab-based comparison of d2-gaboxadol 7,7 at 6-30 mg/kg and gaboxadol at 6-50 mg/kg. White is - top row - gaboxadol at 6, 10, 20, 30, 40 and 50 mg/kg, and - bottom row - significant drug for d2-gaboxadol at 6, 10, 20 and 30 mg/kg -Represents the spatial domain of induction activation. As described herein, robust activation of the dorsolateral and ventral anterior cingulate cortex (ACAd and ACAv) was observed with 10 and 20 mg/kg of gaboxadol as well as 6 mg/kg of d2-gaboxadol, but this The response is strongly attenuated with d2-gaboxadol at doses greater than or equal to 10 mg/kg as well as with gaboxadol at doses greater than or equal to 30 mg/kg. This comparison is further quantified in FIGS. 18 and 19 .
Figure 17 depicts a pharmacomab-based comparison of d2-gaboxadol 7,7 at 6 to 30 mg/kg and gaboxadol at 6 to 50 mg/kg. White is - top row - gaboxadol at 6, 10, 20, 30, 40 and 50 mg/kg, and - bottom row - significant drug for d2-gaboxadol at 6, 10, 20 and 30 mg/kg -Represents the spatial domain of induction activation. As described in the text, strong activation of the basal ganglia (CP) is observed only at higher doses of 30, 40 and 50 mg/kg for gaboxadol, but already at only 10 mg/kg for d2-gaboxadol. but not at 20 and 30 mg/kg. This comparison is further quantified in FIG. 19 .
18 shows quantification of pharmacomab-based comparisons of d2-gaboxadol 7,7 at 6-30 mg/kg and gaboxadol at 6-50 mg/kg in selected brain regions shown in FIGS. 16-17. do. Increases in c-fos+ cell numbers in drug-treated mice are expressed as percentages of control saline-treated mice for selected brain regions: A) lower limbic system (ILA), B) medial orbital (ORBm), C) anterior subject Conference dorsal segment (ACAv). In the left panel the concentration of d2-gaboxadol is provided below the graph, aligned for d2-gaboxadol and gaboxadol. In the right panel, the concentrations of d2-gaboxadol are provided above each graph, the concentrations of gaboxadol are provided below each graph, and the dose curves, d2-gaboxadol 6 mg/kg to gaboxadol 10 mg/kg, d2-gaboxadol 10 mg/kg, gaboxadol 20 mg/kg, d2-gaboxadol 20 mg/kg, gaboxadol 30 mg/kg, , finally aligning d2-gaboxadol 30 mg/kg with gaboxadol 40 mg/kg, shifted to approximately match the responses.
19 shows quantification of pharmacomab-based comparisons of d2-gaboxadol 7,7 at 6-30 mg/kg and gaboxadol at 6-50 mg/kg in selected brain regions shown in FIGS. 16-17. do. Increases in c-fos+ cell numbers in drug-treated mice are expressed as percentages of control saline-treated mice for selected brain regions: A) the ventral portion of the anterior cingulate (ACAv), B) the entire length (CLA), and C ) basal ganglia (CP). In the left panel the concentration of d2-gaboxadol is provided below the graph, aligned for d2-gaboxadol and gaboxadol. In the right panel, the concentrations of d2-gaboxadol are provided above each graph, the concentrations of gaboxadol are provided below each graph, and the dose curves, d2-gaboxadol 6 mg/kg to gaboxadol align to 10 mg/kg, 10 mg/kg of d2-gaboxadol to 20 mg/kg of gaboxadol, 20 mg/kg of d2-gaboxadol to 30 mg/kg of gaboxadol, Finally, d2-gaboxadol 30 mg/kg was aligned to gaboxadol 40 mg/kg, shifting the responses to approximate agreement.
Figure 20 depicts a pharmacomab-based comparison of d6-gaboxadol at 6, 10 and 20 mg/kg and gaboxadol at 6, 10 and 20 mg/kg. Top: White indicates spatial regions of significant drug-induced activation. Left 2 panels: regions shown with significantly stronger significant brain activation with d6-gaboxadol 6 mg/kg compared to gaboxadol 6 mg/kg pamacomab are the periolfactory cortex (PERI) and central amygdala (CEA) ). Middle 2 panels: regions shown with significantly stronger significant brain activation at d6-gaboxadol 10 mg/kg compared to gaboxadol 10 mg/kg pamacomab are the prickly pear cortex (PIRI) and the laminar nuclear demarcation striatum ( BST) included. Right two panels: regions shown with significantly stronger significant brain activation at d6-gaboxadol 20 mg/kg compared to gaboxadol 20 mg/kg pamacomab include the BST and basal ganglia (CP. Bottom: d6-Gaboxadol at 6 mg/kg (left two histograms), 10 mg/kg (middle two histograms) and 20 mg/kg (right two histograms) and pharmacomab-based gaboxadol Quantification of comparison.The increase in the number of c-fos+ cells in drug-treated mice is expressed as a percentage of control saline-treated mice for each group: d6-gaboxadol data are shown as black bars and gaboxadol Data are shown as light gray bars, statistical differences between d2-gaboxadol 6 mg/kg and gaboxadol 6 mg/kg or 10 mg/kg are marked with asterisks above the corresponding bar graphs, where <0.05, < FDR-corrected q values of 0.01 and <0.001 are marked with *, ** and ***, respectively.
Figure 21 shows further quantification of pharmacomab-based comparisons of 6 mg/kg gaboxadol and d6-gaboxadol across the brain regions with the greatest differences at these drug doses: BST rhomboid muscle nucleus (BSTrh In addition to the anterior part (BSTa) of the stratum nuclear demarcation striatum, including the ) and auditory plaques (LC), both the gustatory (GU), instinctive (VISC), and agranular lateral temporal cortex (AI) dorsal (AId) and posterior (AIp) Association cortex, including all, temporal association (TEa) areas and forefoot (CLA). The increase in the number of c-fos+ cells in drug-treated mice is shown as a percentage of control saline-treated mice with gaboxadol data shown as black bars and d6-gaboxadol data shown as light gray bars. Statistical differences between d2-gaboxadol 6 mg/kg and gaboxadol 6 mg/kg or 10 mg/kg are marked with asterisks above the corresponding bar graphs, where ANOVA and FDR-corrected q of <0.05 and <0.01 Values are marked with * and ** respectively.
22 shows further quantification of pharmacomab-based comparisons of gaboxadol at 10 mg/kg and d6-gaboxadol across the brain regions with the greatest differences at these drug doses: BST rhomboid muscle nucleus (BSTrh ), anterior cingulate cortex (ACA) including dorsal (ACAd) and ventral (ACAv) portions of the stratum nucleus accumbens striatum (BSTa), limbic subcortex (ILA), taste (GU) , Instinctive (VISC), agranular lateral temporal cortex (AI) association cortical areas, including both dorsal (AId) and posterior (AIp), temporal association (TEa) areas and forefoot (CLA). The increase in the number of c-fos+ cells in drug-treated mice is shown as a percentage of control saline-treated mice with gaboxadol data shown as black bars and d6-gaboxadol data shown as light gray bars. Statistical differences between d2-gaboxadol 7,7 6 mg/kg and gaboxadol 6 mg/kg or 10 mg/kg are marked with an asterisk above the corresponding bar graph, where ANOVA and FDR of <0.01 and <0.001 -corrected q values are marked with ** and ***, respectively.
23 shows further quantification of pharmacomab-based comparisons of 20 mg/kg gaboxadol and d6-gaboxadol across the brain regions with the greatest differences at these drug doses: BST rhomboid muscle nucleus (BSTrh ), the anterior part of the striatum demarcation striatum (BSTa), the BST principal nucleus (BSTpr), the BST interstitial nucleus (BSTif), and the BST transverse nucleus (BSTtr), including the BST oval nucleus (BSTov). ), the posterior part of the striatum (BSTp) including the nucleus accumbens, the ventral striatum (STRv) including the posterior tubercle (OT) and the nucleus accumbens (ACB), and the cyanus (LC), the basal ganglia (CP). The increase in the number of c-fos+ cells in drug-treated mice is shown as a percentage of control saline-treated mice with gaboxadol data shown as black bars and d6-gaboxadol data shown as light gray bars. Statistical differences between d2-gaboxadol 7,7 6 mg/kg and gaboxadol 6 mg/kg or 10 mg/kg are marked with asterisks above the corresponding bar graphs, where <0.05, <0.01 and <0.001 ANOVA and FDR-corrected q values are marked with *, ** and ***, respectively.
24 shows d6-Gaboxadol (short dashed line), d2-Gaboxadol 7,7 (long dashed line) and gaboxadol (short-dashed line) compared to control mice treated only with saline (vehicle) injection (solid line). Shows the time course of onset of sedation in mice induced by long dashed lines). Movement of the mouse (meters per minute) is quantified on the y-axis, while time (minutes) is plotted on the x-axis. The data show that the onset of d6-gaboxadol-induced sedation at 11 min (reflected by the onset of immobility) is faster than that of d2-gaboxadol at 13 to 14 min, while d6-gaboxadol and d2 -Gaboxadol-induced onset of sedation of both was shown to be earlier than that of gaboxadol at 15 minutes. Statistical significance is marked with an asterisk, where ANOVA p values of <0.05, <0.01 and <0.001 are marked with *, ** and ***, respectively.
25 depicts an exemplary ketamine dose-curve pharmacomab. White indicates spatial regions of significant drug-induced activation. The very broad activation pattern evoked by ketamine at 10 mg/kg included the following anatomical structures: Cortex: anterior cingulate (ACA), limbic prelimbic (PL) and infralimbic (ILA) cortices, cucurbital cortex (PIR), associative instinctive (VISC), gustatory (GU), agranular dorsal cortex (AIp) cortical areas, occipital lobe (RSP), motor (MO), vocalization (SS), auditory (AUD), visual (VIS) ), temporal association (Tea), periolfactory (PERI) and internal olfactory (ENT), and extraolfactory (ECT) cortical regions; Basal ganglion: nucleus accumbens (ACB), collateral septum (LS), anterior segment of striatum demarcated nucleus accumbens (BSTa), cortical amygdala and central amygdala (CEA); midline thalamus: paraventricular nucleus (PVT), dorsomedial intermediodorsal nucleus (IMB), medial central nucleus (CM), and rhomboid nucleus (RH); midbrain: geniculate complex (MG) and periaqueductal gray (PAG); Brain stem: blue spot (LC).
26 depicts an exemplary side-by-side comparison between gaboxadol and ketamine pharmacomab. White indicates spatial regions of significant drug-induced activation (green for inhibition, which is very rare without clear anatomical significance). Gaboxadol at 10 mg/kg (left panel) induced extensive brain activation very similar to that of ketamine at 10 mg/kg (right panel). These include: Cortex: anterior cingulate (ACA), limbic prefrontal (PL) and hypolimbic (ILA) cortices, cutaneous cortex (PIR), associational instinctive (VISC), gustatory (GU), agranular lateral gyrus Inferior cortical (AIp) cortical areas, occipital lobe (RSP), motor (MO), vocal (SS), auditory (AUD), visual (VIS), temporal association (TEa), periolfactory (PERI), and enolence (ENT) , and extraolfactory (ECT) cortical regions; Basal ganglion: nucleus accumbens (ACB), anterior segment of the striatum demarcated nucleus accumbens (BSTa), cortical amygdala and central amygdala (CEA); Central thalamus: paraventricular nucleus (PVT), dorsomedial hepatic nucleus (IMB), medial central nucleus (CM), and rhomboid nucleus (RH); midbrain: patella complex (MG) and peraqueductal gray matter (PAG); Brain stem: blue spot (LC).
27A-27B show examples of synergistic effects obtained by co-administration of gaboxadol and ketamine. White indicates spatial regions of significant drug-induced activation (green for inhibition, which is very rare without clear anatomical significance). Gaboxadol at 3 mg/kg (left panel); Ketamine at 6 mg/kg (middle panel); Gaboxadol at 3 mg/kg and ketamine at 6 mg/kg (right panel). These include: Cortex: anterior cingulate (ACA), limbic prefrontal (PL) and hypolimbic (ILA) cortices, cutaneous cortex (PIR), associational instinctive (VISC), gustatory (GU), agranular lateral gyrus Inferior cortical (AIp) cortical areas, occipital lobe (RSP), motor (MO), vocal (SS), auditory (AUD), visual (VIS), temporal association (TEa), periolfactory (PERI), and enolence (ENT) , and extraolfactory (ECT) cortical regions; Basal ganglion: nucleus accumbens (ACB), anterior segment of the striatum demarcated nucleus accumbens (BSTa), cortical amygdala and central amygdala (CEA); Central thalamus: paraventricular nucleus (PVT), dorsomedial hepatic nucleus (IMB), medial central nucleus (CM), and rhomboid nucleus (RH); midbrain: patella complex (MG) and peraqueductal gray matter (PAG); Brain stem: blue spot (LC).
28 shows exemplary results of a forced swim test. Both ketamine (circle symbols) and gaboxadol (triangle symbols) significantly reduced the time spent floating (floating) during the 6-minute forced swim compared to the control vehicle-treated group.
29 depicts an exemplary lithium dose-curve pharmacomab. White indicates spatial regions with significant lithium-induced induction of c-fos activity in the mouse brain. The extensive activation patterns induced by lithium with increasing dose were confined to the following anatomical structures, for example: cortex: prelimbic (PL) and hypolimbic (ILA) cortices, cucurbital cortex (PIR), Associational instinctive (VISC), gustatory (GU), agranular lateral dorsal cortex (AIp) cortical areas, occipital lobe (RSP), motor (MO), vocal (SS), auditory (AUD), visual (VIS), temporal association (Tea), periolfactory (PERI) and entorhinal (ENT), and exoolfactory (ECT) cortices; Basal ganglion: nucleus accumbens (ACB), anterior segment of the striatum demarcated nucleus accumbens (BSTa), cortical amygdala and central amygdala (CEA); Central thalamus: paraventricular nucleus (PVT), dorsomedial hepatic nucleus (IMB), medial central nucleus (CM), and rhomboid nucleus (RH); midbrain: geniculate complex (MG); Brain stem: blue spot (LC).
30 shows exemplary lithium-induced brain activation similar to that of gaboxadol. White indicates spatial regions of significant lithium-induced induction of c-fos activity in the mouse brain. The broader activation pattern evoked by lithium at a dose of 300 mg/kg (top row; human equivalent dose of about 1500 mg) is comparable to that of gaboxadol at 20 mg/kg (bottom row; human equivalent dose of about 100 mg). Appears similar to the effect, which includes the following anatomical structures: Cortex: Inferior Lung Line (ILA) Cortex, Purkinje Cortex (PIR), Associated Instinctive (VISC), Gutatory (GU), Agranulolateral Dorsal Dorsal Cortex (AIp) cortical areas, occipital lobe (RSP), motor (MO), audible voice (SS), auditory (AUD), visual (VIS), temporal association (Tea), periolfactory (PERI) and enolence (ENT), and exoolfactory (ECT) cortex; Basal ganglion: nucleus accumbens (ACB), anterior segment of the striatum demarcated nucleus accumbens (BSTa), cortical amygdala and central amygdala (CEA); Central thalamus: paraventricular nucleus (PVT), dorsomedial hepatic nucleus (IMB), medial central nucleus (CM), and rhomboid nucleus (RH); midbrain: geniculate complex (MG); Brain stem: blue spot (LC).
31 depicts an exemplary synergistic effect from co-administration of gaboxadol with subnormal doses of lithium. White indicates spatial regions of induction of significant lithium-induced c-fos activity in the mouse brain. Neither 85 mg/kg of lithium (upper column, human equivalent dose of approximately 425 mg) nor 3 mg/kg of gaboxadol (intermediate column, human equivalent dose of approximately 15 mg) did not induce any brain activation by themselves. , the combination of these doses induced marked and widespread activation (bottom row), suggesting a synergy between the two compounds within several anatomical brain structures, including: cortex: infralimbic (ILA) cortex , gourd cortex (PIR), associative instinctive (VISC), taste (GU), agranular dorsal cortex (AIp) cortical area, occipital lobe (RSP), motor (MO), voice (SS), auditory (AUD), visual (VIS), temporal association (Tea), periolfactory (PERI) and entorhinal (ENT), and exoolfactory (ECT) cortices; Basal ganglion: nucleus accumbens (ACB), anterior segment of the striatum demarcated nucleus accumbens (BSTa), cortical amygdala and central amygdala (CEA); Central thalamus: paraventricular nucleus (PVT), dorsomedial hepatic nucleus (IMB), medial central nucleus (CM), and rhomboid nucleus (RH); midbrain: geniculate complex (MG); Brain stem: blue spot (LC). Weak inhibitory patterns (green) observed in the basal ganglia (CP) and hippocampus (HIPP) suggest mild sedation induced by both compounds.
32A depicts exemplary synergistic and additive brain activation effects of co-administration of gaboxadol and standard doses of lithium. White indicates spatial regions of induction of significant lithium-induced c-fos activity in the mouse brain. 150 mg/kg of lithium (upper row; human equivalent dose of about 750 mg) and 6 mg/kg of gaboxadol (middle row; human equivalent dose of about 30 mg) were found to be Although they themselves induced moderate brain activation, including the anterior part of the nuclear demarcation striatum (BSTa), the auditory fossa (LC), and some additional cortical regions, the combination of these two doses did not induced significantly more pronounced activations (bottom row), further demonstrating synergistic and additive actions between the two compounds, including: cortex: inferior interneuronal (ILA) cortex, cucurbital cortex (PIR), associative instinctive (VISC), taste (GU), agranular lateral dorsal cortex (AIp) cortical areas, occipital lobe (RSP), motor (MO), voice (SS), hearing (AUD), vision (VIS), temporal association (Tea) , periolfactory (PERI) and internal olfactory (ENT), and external olfactory (ECT) cortices; Basal ganglion: nucleus accumbens (ACB), anterior segment of the striatum demarcated nucleus accumbens (BSTa), cortical amygdala and central amygdala (CEA); Central thalamus: paraventricular nucleus (PVT), dorsomedial hepatic nucleus (IMB), medial central nucleus (CM), and rhomboid nucleus (RH); midbrain: geniculate complex (MG); Brain stem: blue spot (LC). Weak inhibitory patterns (green) observed in the basal ganglia (CP) and hippocampus (HIPP) suggest mild sedation induced by both compounds.
32B depicts exemplary synergistic and additive brain activation effects of co-administration of gaboxadol and standard doses of lithium. White indicates spatial regions of significant lithium-induced activation in the mouse brain. 200 mg/kg of lithium (upper row; human equivalent dose of about 1000 mg) and 6 mg/kg of gaboxadol (middle row; human equivalent dose of about 30 mg) were Although they induced moderate brain activation by themselves, including the anterior portion of the Vnitial 20 min, treatment with d-amphetamine induced a burst of locomotion in vehicle-treated animals (upper dark blue line); This was not controlled by 14.1 mg/kg lithium alone (top second orange line), and was only mild (Anova p-value = 0.007, Fisher's PLSD test p = 0.6), whereas the combination of 14.1 mg/kg lithium and 3 mg/kg gaboxadol (lower light blue) kinetics demonstrating synergy between the two molecules (Anova p value = 0.007, Fisher's PLSD test (p = < 0.01) showed significant control.
33 depicts the results of an experiment on the effects of lithium, gaboxadol and their combination on amphetamine-induced hyperkinesia.
Figure 34 shows d2-gaboxadol 7,7 at 6 mg/kg, lithium at 150 mg/kg, and d2-gaboxadol 7,7 and 150 mg/kg at 6 mg/kg in the nucleus accumbens (ACB). Shows pharmacomab-based comparison of combinations of kg of lithium.
Figure 35 shows d2-gaboxadol 7,7 at 6 mg/kg, lithium at 150 mg/kg, and d2-gaboxadol 7 at 6 mg/kg in the anterior part of the striatum (BSTa) of the striatum nuclear demarcation. A pharmacomab-based comparison of combinations of 7 and 150 mg/kg of lithium is shown.
36 shows d2-gaboxadol 7,7 at 6 mg/kg, lithium at 150 mg/kg, and d2-gaboxadol 7,7 and 150 mg at 6 mg/kg in the ventral tegmental area (VTA). Pharmacomab-based comparison of combinations of /kg of lithium is shown.
Figure 37 shows blue spots (LC), 6 mg/kg d2-gaboxadol 7,7, 150 mg/kg lithium, and 6 mg/kg d2-gaboxadol 7,7 and 150 mg/kg A pharmacomab-based comparison of combinations of lithium is shown.
FIG. 38 shows d2-Gaboxadol 7,7 and Gaboxadol 7,7 and Gaboxadol in the identified brain regions: nucleus accumbens (ACB), anterior portion of the striatum demarcation (BSTa), ventral tegmental area (VTA), and auditory fossa (LC). Quantification of pharmacomab-based comparisons of stone 6 mg/kg, lithium 150 mg/kg and d2-gaboxadol 7,7, a combination of gaboxadol and lithium is shown.

Reference will now be made in detail to each embodiment of the present invention. These embodiments are provided as an illustration of the invention, and are not intended to be limiting. In fact, those skilled in the art can understand that various modifications and variations may be made thereto upon reading this specification and looking at the drawings.

Definitions and Certain Specific Embodiments

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure herein belongs.

As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly dictates otherwise.

In certain embodiments, as used herein, the term “about” or “approximately” means within an acceptable error range for a particular value, as determined by one of ordinary skill in the art, how the value is measured or determined, i.e. , will depend in part on the limitations of the measurement system.

In certain embodiments, the term “about” or “approximately” when used to modify a numerical value means plus or minus 20%, 10%, 5%, 1%, or 0.1% of that value. In certain embodiments, the term “about” means plus or minus 10% of a specified value. In certain embodiments, the term “about” means plus or minus 5% of a specified value. In certain embodiments, the term “about” means plus or minus 1% of a specified value. In certain embodiments, the term “about” means plus or minus 0.1% of a specified value.

In certain embodiments of the methods of treating a mental disorder as provided herein, when the deuterated gaboxadol is administered in combination with a second therapeutic agent (different from the deuterated gaboxadol) to treat the mental disorder, the deuterated gaboxadol Gaboxadol and the second therapeutic agent may be administered simultaneously, sequentially or concurrently and may be in the same or separate compositions. In certain embodiments, the administration of deuterated gaboxadol and another compound, such as lithium, is “contemporaneous.”

In certain embodiments, the deuterated gaboxadol is administered within about 5 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours of administration of the other compound. Administration of deuterated gaboxadol and the other compound is "simultaneous" if administered to a patient in need thereof within about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours. In certain embodiments, deuterated gaboxadol is administered to a patient in need thereof within about 2 hours of administration of the other compound.

In certain embodiments, the administration of deuterated gaboxadol and the other compound is “simultaneous”. The term "simultaneously" is used in the general sense of at the same time.

In certain embodiments, the administration of deuterated gaboxadol and the other compound is “sequential,” also referred to as “sequential,” “sequential,” administration, and the like. The terms “sequential” and “sequentially” are used in the general sense of sequentially. Sequential courses of administration can also be synchronous.

In certain embodiments, the simultaneous administration of another compound and deuterated gaboxadol may include separate dosages of separate pharmaceutical compositions or combined dosages of the other compounds administered simultaneously with the deuterated gaboxadol in a single pharmaceutical composition. there is.

In certain embodiments, the subject in the methods of treatment provided herein is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, or barboon ( baboon). The terms "subject" and "patient" are used interchangeably. In certain embodiments, the subject is a human suffering from a mental disorder, such as depression or bipolar disorder. In certain embodiments, the subject is a human. In certain embodiments, the human is a pediatric human. In certain embodiments, the subject is an adult human.

For purposes of explanation herein, the terms “ring carbon deuterated gaboxadol” and “deuterated gaboxadol” and “deuterated gaboxadol compounds” refer to compounds enriched with deuterium in excess of the naturally occurring abundance of deuterium. (i.e., deuterium occurs in place of hydrogen in all molecules in nature at approximately 0.0156%, which is naturally abundant deuterium), and at one or more ring carbon positions of the tetrahydro-pyridine ring of gaboxadol (i.e., 4, 5 and 7 positions) are used interchangeably to refer to the form of gaboxadol that has a deuterium atom. Thus, deuterated gaboxadol has 2, 4 or 6 deuteriums, including 1 to 6 deuteriums bonded to the ring carbons, preferably 1, 3 or 5 deuteriums bonded to the ring carbons. can have The term "d1-gaboxadol" refers to a deuterated gaboxadol having one deuterium atom bonded to a tetrahydro-pyridine ring carbon atom. The term "d2-gaboxadol" refers to a deuterated gaboxadol having two deuterium atoms bonded to the tetrahydro-pyridine ring carbon atoms. The term "d3-gaboxadol" refers to a deuterated gaboxadol having three deuterium atoms bonded to the tetrahydro-pyridine ring carbon atoms. The term "d4-gaboxadol" refers to a deuterated gaboxadol having four deuterium atoms bonded to the tetrahydro-pyridine ring carbon atoms. The term “d5-gaboxadol” refers to a deuterated gaboxadol having 5 deuterium atoms bonded to the tetrahydro-pyridine ring carbon atoms. The term "d6-gaboxadol" refers to a deuterated gaboxadol having 6 deuterium atoms bonded to the tetrahydro-pyridine ring carbon atoms. As used herein, ring carbon deuterated gaboxadol and deuterated gaboxadol may be considered generic terms (also "types") encompassing these various deuterated forms of gaboxadol.

As used herein, a "form" of deuterated gaboxadol can be distinguished from a "species" of deuterated gaboxadol as follows: "Form" is the number of deuterium fused to ring carbon atoms in a gaboxadol molecule. number, i.e. 1 to 6 deuterium atoms. Thus, d1-gaboxadol is a form of gaboxadol. This form of gaboxadol can contain up to six different deuterated species, as shown in FIG. 1A . For purposes of this invention and description herein, each enantiomer of cyclic carbon deuterated gaboxadol is counted as a separate species. Typically, mass spectrometry can distinguish forms d1-, d2-, etc. by mass. However, it is understood that the form of deuterated gaboxadol may include a variety of species that are not distinguished by mass.

The term "gaboxadol" alone, without any limitation, indicates that the gaboxadol is a non-deuterated gaboxadol.

A composition of deuterated gaboxadol can be described as a percentage of a particular deuterated form of gaboxadol in the composition. For example, a composition in which 50% d6-gaboxadol is a composition in which half of the gaboxadol molecules in the composition are d6-gaboxadol and half of the molecules are another form of deuterated gaboxadol or a non-deuterated gaboxadol. Indicates that it is a copy stone.

In another example, the composition of deuterated gaboxadol is about 80% d6-gaboxadol, about 18% d5-gaboxadol and about 2% other forms of deuterated or non-deuterated gaboxadol. It may be a gaboksadol.

In certain embodiments, a method of treatment provided herein is one that achieves a therapeutic result, eg, which relieves to some extent one or more symptoms of the disease or condition being treated, wherein a therapeutically effective amount is sufficient to achieve the therapeutic result. do. In certain instances, the result is reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. In some embodiments, an effective amount is a dosage effective to relieve, reduce, significantly reduce, or eliminate symptoms generally associated with bipolar disorder or mania. In certain instances, an “effective amount” for therapeutic use is the amount of a composition comprising an agent according to the present disclosure necessary to provide a clinically significant reduction in disease. In certain embodiments, an “effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study.

In certain embodiments, an “effective amount” or “therapeutically effective amount” of deuterated gaboxadol is the amount of a single dose of deuterated gaboxadol sufficient to treat a psychiatric disorder.

In certain embodiments, an "effective amount" or "therapeutically effective amount" of gaboxadol or deuterated gaboxadol is a dosage combination of gaboxadol, deuterated gaboxadol, or the two that is sufficient to treat a mental disorder. is the amount of two doses of

In certain embodiments, the method of treatment is to achieve an improvement that is a reduction in one or more of the symptoms or underlying pathology of a mental disorder.

In certain embodiments, the method of treatment produces an improvement in function the next day, e.g., a beneficial effect on at least one symptom, for at least a period of time, e.g., at least about 6 hours, at least about 12 hours, at least about 24 hours, etc. and to achieve improvement that rapidly alleviates the patient's symptoms.

In certain embodiments of the methods of treatment provided herein, administration is oral or intranasal.

In certain embodiments, a “patient in need thereof” or “subject in need thereof” is a patient or subject who has been diagnosed with, is at risk of, or has symptoms of a mental disorder.

As used herein, unless otherwise specified, the term “therapeutic resistance” is used as understood by those skilled in the art. In certain embodiments, treatment resistant depression is depression that exhibits a lack of response to treatment after at least one treatment period in which the antidepressant is administered for about 6 weeks.

In certain embodiments, the method of treatment is administered by oral, intraduodenal, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical, rectal, or any other suitable route of administration. includes Administration techniques optionally used with the agents and methods described herein are described, eg, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; [Pergamon]; and [Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.]. In some embodiments, the agents and compositions described herein are administered orally.

In certain embodiments, the pharmaceutically acceptable carrier is a federal or state regulatory agency, such as the Federal Food, Drug and Cosmetic Act, which has undergone premarket review and has been approved by the FDA. ) under sections 204(s) and 409 of the GRAS list or similar list, the United States Pharmacopoeia or the Generally Recognized Pharmacopoeia for use in animals or more particularly in humans.

In certain embodiments, “treat,” “treatment,” or “treating” according to the present invention is intended to reverse, alleviate, ameliorate, inhibit, slow, or stop the progression or severity of a mental disorder. can In certain embodiments, "treat", "treatment" or "treating" for a mental disorder refers to reducing or alleviating at least one symptom of a mental disorder, one or more symptoms or clinical indicators of a mental disorder. reducing, reducing or arresting the progression of a mental disorder, ameliorating one or more symptoms or indicators of a mental disorder, stopping or at least slowing the worsening or progression of a symptom, compared to what would be expected in the absence of treatment. achieving, alleviation of one or more symptom(s), diminishment of extent of disease, achieving a stabilized (i.e., not worsening) disease state, delay or slowing of disease progression, amelioration or palliation of disease state, remission ( (whether partial or total), reducing mortality, palliative care that alleviates the clinical symptoms of a mental disorder in a subject suffering from a mental disorder, halting or reducing the development of a mental disorder or at least one clinical or subclinical symptom thereof; and/or a mathematically significant reduction in symptoms of a psychiatric disorder. Permanent curative treatment may occur, but is not required herein to achieve “treatment”. Treatment can be carried out by administering a drug to a patient or subject in need thereof. Treatment may include a single administration of a drug, multiple administrations of a drug over time, simultaneous or sequential administration of multiple drugs over a time period, administration of multiple doses of a drug, or appropriate combinations of the foregoing.

In certain embodiments, a method for preventing a mental disorder in a patient in need thereof is provided, comprising administering to the patient an effective amount of deuterated gaboxadol.

In certain embodiments, the patient is at risk of developing a mental disorder, as indicated, for example, by a test diagnosis for such risk. In certain embodiments, “managing,” “managing,” and “managing” a mental disorder refers to preventing a recurrence of a mental disorder in a patient already suffering from the disorder, and/or maintaining remission by a patient suffering from the disorder. extending the time, or adjusting the threshold, development and/or duration of the disorder, or altering the way the patient responds to the disorder.

"Unit dosage form" or "UDF" means a physically fixed unit dose of a formulation conveniently administered in unit form (eg, the dose does not need to be measured or adjusted prior to consumption). A patient may consume more than one UDF at a time.

In certain embodiments, a "rapid antidepressant", "rapid-acting antidepressant", "quick relief", "rapid relief" or "short-acting antidepressant" is defined as within 24 hours, preferably within about 6 hours, of first treatment with the drug. , most preferably within about 180 minutes of initial treatment, refers to an agent capable of providing effective treatment of depression (e.g., delivering therapeutic relief) and (as can be observed objectively or subjectively) ), also referred to herein as "rapid relief" or "rapid relief" of depressive symptoms, in certain embodiments. Providing effective treatment that provides relief as described above may also be referred to as providing improvement in function the next day.

In certain embodiments, a "rapid anti-suicide", "rapid-acting anti-suicide" or "short-acting anti-suicide" is within 24 hours, preferably within about 6 hours, most preferably within 24 hours of first treatment with the drug. Refers to an agent capable of providing effective treatment of suicidal ideation (e.g., delivering therapeutic relief), within about 180 minutes of treatment (as can be observed objectively or subjectively), which is also In certain embodiments, referred to herein as "rapid relief" or "rapid relief" of suicidality. Providing effective treatment that provides relief as described above may also be referred to as providing improvement in function the next day.

As used herein, unless otherwise specified, the term “synergistic” or “synergistic” or “synergistically” or “synergistically” refers to the therapeutic effect of a combination of deuterated gaboxadol and another agent. "synergistic" is consistent with its art-accepted meaning and refers to a therapeutic effect when treated with a combination of deuterated gaboxadol and another compound, wherein the therapeutic effect of the compounds administered in combination is If not, it is greater than the sum of their individual treatment effects.

For example, in certain embodiments, a combination of lithium and deuterated gaboxadol may exhibit a synergistic effect in treating, preventing, and/or managing a psychiatric disorder. Several types of synergism are recognized by those skilled in the art. By way of example, some synergism can be recognized in a 1 + 1 = 3 fashion, where the resulting effect of the combination exceeds the additive of the compounds administered individually. As another example, another synergism is 0 + 0 = 1 of a kind, where the resulting effect of the combination exceeds the additive of the compounds administered individually, which proves ineffective individually (at given test doses). Both compounds demonstrate efficacy when administered together. The latter synergism is considered particularly pronounced when the test compounds are not known to act through similar or related pathways.

In certain embodiments, the additional combination of the compound and deuterated gaboxadol is effective in treating, preventing and/or managing a psychiatric disorder.

As used herein, "c-fos signaling", "c-fos activity", "c-fos expression", "c-fos activation", "c-fos gene expression" are used interchangeably and , eg, immunohistochemistry, in situ hybridization of c-fos-specific probes, GFP expression in c-fos-GFP mice, or pharmacomapping as described herein (Example 6- 19) refers to the activation in the brain of expression of the outpost gene (IEG), which is c-fos.

As used herein, unless otherwise indicated, the term “substandard dose” for lithium refers to adult humans who are expected to lack therapeutic efficacy in lithium monotherapy for bipolar disorder, depression, treatment-resistant depression, and suicidal tendencies. It refers to human dosages in the range of about 50 to about 600 mg.

As used herein, unless otherwise indicated, the term "standard dose" for lithium is intended to be expected to be therapeutically effective in lithium monotherapy for bipolar disorder, depression, treatment-resistant depression, and suicidal tendencies (adults for humans) refers to human doses in the range of 600 to 1800 mg of lithium carbonate, with a maximum daily dose of 2400 mg.

In certain embodiments, a mental disorder is a medical problem involving significant changes in thinking, feeling and/or behavior, and/or problems and/or difficulties with functioning in social, work or family activities. Mental disorders include, but are not limited to, bipolar disorder, schizophrenia, borderline personality disorder, depression, major depressive disorder, treatment resistant depression, generalized anxiety disorder, substance abuse, addictive disorder including alcohol abuse, behavioral addiction, suicide Ideation, acute suicidal tendencies, risk of self harm, agoraphobia, anorexia nervosa, anxiety disorders, attention deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), binge eating disorder, bipolar disorder, bulimia nervosa, dementia, eating disorders, obsessive-compulsive disorder (OCD), panic disorder, persistent depressive disorder (dysthymic disorder), personality disorder, post-traumatic stress disorder (PTSD), postpartum depression, schizophrenia, social anxiety disorder, social and other specific phobias, or severe sadness, excessive worry, severe mood swings, difficulty distinguishing reality from delusions, isolation and avoidance from friends or social activities; Sudden changes in sex drive or sleeping habits or eating habits; alcohol or drug abuse; and conditions associated with or manifesting one or more symptoms, including suicidal thoughts.

"Suicidal ideation", also described as "suicidalness", "suicidal ideation", "suicidal urge", "suicidal compulsion", "suicidalism" and "suicidal propensity", is a recognized condition. In certain embodiments of this condition, the patient has one or more of the following: subjective wish to die, passive and active thoughts of attempting suicide, considerable duration and frequency of thoughts, lack of control, lack of deterrence, preparatory behavior for suicide attempt, and others. Symptom. The condition can be assessed by scoring on a scale for suicidal ideation (Beck et al. J Consult Clin Psychol 1979; 47:343-352). In certain embodiments, suicidal ideation includes thinking about or having an abnormal preoccupation with suicide. Suicidal ideation ranges in severity from fleeting thoughts to far-reaching thoughts, detailed planning, role-playing (eg, noose and standing on a chair), and incomplete attempts. Suicidal ideation may be associated with major depressive disorder, treatment-resistant depression, disruptive mood dysregulation disorder, major depressive disorder (including major depressive episodes), persistent depressive disorder (dysthymia), premenstrual dysphoric disorder, substance/drug-induced depressive disorder, or another medically Depressive Disorder Due to Condition, Other Specified Depressive Disorder, and Unspecified Depressive Disorder are distinguished from patients with a condition diagnosed (under the DSM-V), in which there is potential for overlap.

In certain embodiments, a patient “at risk of suicide” is a human subject with a clinically or subjectively assessed short-term or medium-term risk who is actively moving toward self-harm with a risk of death. In certain embodiments, a patient at risk of suicide is a patient diagnosed according to the DSM-V or other criteria as experiencing suicidal ideation, acute suicidal tendencies, recurrent thoughts of death, and/or suicide attempts. Diagnoses of depression, major depressive disorder, treatment-resistant depression, bipolar disorder, mania, and other disturbing psycho-social conditions do not necessarily elicit the term "suicidal risk", but distinct subsets of these patients have been identified separately as being at risk of suicide. It can be.

In certain embodiments, the person at risk of suicide has not been diagnosed with any psychiatric disorder, including major depression.

In certain embodiments, the person at risk of suicide does not have major depression.

In certain embodiments, the person at risk of suicide does not have Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, Fragile X syndrome, or Angelman syndrome.

In certain embodiments, the person at risk of suicide is being treated with an antidepressant.

deuterated gaboxadol

ring carbon deuterated gaboxadol (Gaboxadolum or THIP (4,5,6,7-tetrahydroisooxazolo(5,4-c) pyridin-3-ol); C ₆ H ₈ N ₂ O ₂ ; Cas number: 64603-91-4; PubChem CID: 3448)), compared to non-deuterated gaboxadol, is believed to be useful for treating psychiatric disorders, as shown by induction of brain activation in specific regions. It has beneficial properties, including enhanced neurological activity, such as (see Examples 7 and 8 hereinbelow).

In one aspect, the present invention relates to cyclic carbon deuterated gaboxadol, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, methods of making such compounds, and methods of use thereof.

In one aspect, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof:

In the above formula, R4, R4', R5, R5', R7 and R7' are independently H or D,

At least one of R4, R4', R5, R5', R7 and R7' is D.

Deuterated gaboxadol is sometimes referred to herein as d n -gaboxadol, where n represents the number of D's at a site selected from R4, R4', R5, R5', R7 and R7' in the compound. Unless further indicated by context or implication, D may be at any site selected from R4, R4', R5, R5', R7 and R7'. A particular form of deuterated gaboxadol may be referred to herein as dn-gaboxadol in which a deuterium atom is followed by the ring carbon position of the tetrahydro-pyridine ring of gaboxadol. For example, when deuterium is incorporated in R7 and R7', the deuterated gaboxadol may be referred to herein as d2-gaboxadol 7,7.

d1-Gaboxadol has six species as shown in Figure 1A .

d2-Gaboxadol has 15 species as shown in FIG. 1B .

d3-Gaboxadol has 20 species as shown in Figure 1c .

d4-Gaboxadol has 15 species as shown in Figure 1d .

d5-Gaboxadol has six species as shown in FIG. 1E .

d6-Gaboxadol has only one species as shown in FIG. 1F .

In certain embodiments, if none of R4, R4', R5, and R5' is H, then neither R7 nor R7' is D.

In certain embodiments, if R4, R4', R5, and R5' are all D then at least one of R7 and R7' is D.

In certain embodiments, R4, R4', R5, R5', R7 and R7' are all D, and thus the deuterated gaboxadol is d6-gaboxadol. In a preferred embodiment, the deuterated gaboxadol is d6-gaboxadol.

It will be appreciated that some variation in the abundance of natural isotopes in synthesized compounds typically occurs depending on the origin of the chemical used in the synthesis. Thus, formulations of Formula I will inherently contain small amounts of isotopologues at each atom of the molecule. In particular, the compounds of the present invention may contain isotopes at the sites indicated by H, N, O and carbon. Generally, such isotopes will be present in the formulation in the presence of their natural isotopes. It is technically possible to enrich or deplete these isotopes relative to their natural abundance. The present invention relates to the modification, enrichment or depletion of said isotopes at these other atoms, as long as the deuteration at one or more of R4, R4', R5, R5', R7 and R7' of Formula I is as described herein. include

It will be appreciated that single deuteration at either position 4, 5 or 7 will create a chiral center at that position. The diversity of stereochemical alternatives increases the variety of species of deuterated gaboxadol disclosed herein.

In another aspect, the present invention provides a composition comprising at least one compound of Formula I or a pharmaceutically acceptable salt thereof.

The compositions of the present invention may contain only one form of deuterated gaboxadol, or may contain more than one form of deuterated gaboxadol, each of which is selected from the compounds shown in FIGS. 1a-1f . The relative proportions of the deuterated forms of gaboxadol will depend on the synthetic method used and the efforts to isolate and purify the form. Exemplary embodiments of the composition are presented elsewhere in this disclosure.

In another aspect, the present invention provides a pharmaceutical composition comprising a composition comprising at least one compound of Formula I or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier.

Compositions comprising deuterated gaboxadol or deuterium-enriched gaboxadol or the foregoing are described in terms of the percentage incorporation of deuterium in place of hydrogen at positions R4, R4', R5, R5', R7 and R7' of the compound of formula I. It can be. The percentage incorporation of deuterium in ring carbon deuterated gaboxadol does not include deuterium bonded to intramolecular heteroatoms. In general, the percent incorporation of deuterium is determined at one or more of positions R4, R4', R5, R5', R7 and R7', out of the total amount of deuterated and non-deuterated molecules, in a sample of a given gaboxadol compound. Refers to the percentage of gaboxadol molecules that have incorporated deuterium. For example, a deuterium incorporation percentage of 1% means that 1% of the compounds of Formula 1 in a given sample contain deuterium at one or more of positions R4, R4', R5, R5', R7 and R7'. Non-deuterated gaboxadol can be distinguished from deuterium-enriched gaboxadol, and the percentage of deuterated gaboxadol can be determined. Deuterated gaboxadol or deuterium-enriched gaboxadol means that the compound gaboxadol is enriched with deuterium in excess of the naturally occurring deuterium abundance (i.e., deuterium is the natural deuterium abundance, about 0.0156 Occurs in place of hydrogen in all molecules in nature as a percentage). In certain embodiments, the percentage incorporation of deuterium is at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%. 90%, 95%, or 98%, or the deuterated gaboxadol is at least 1%, 5%, 10%, 15%, 20% of the total gaboxadol molecules (including deuterated and non-deuterated forms) in the composition. , 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%. 90%, 95% or 98%.

In addition, a formulation of deuterated gaboxadol can be described as a percentage of a particular deuterated form of gaboxadol in the formulation. For example, a formulation in which 50% is d6-gaboxadol has half of the gaboxadol molecules in the formulation being d6-gaboxadol and half of the molecules are another form of deuterated gaboxadol or a non-deuterated gaboxadol. Indicates that it is a copy stone.

In some embodiments, it may be further specified what percentage of a particular form of deuterated gaboxadol is, such as d6-, d5- or d4-gaboxadol. For example, a formulation of deuterated gaboxadol can be about 80% d6-gaboxadol, about 18% d5-gaboxadol, and about 2% gaboxadol or other forms of deuterated gaboxadol. (See Table IV for example). In certain embodiments, the deuterated gaboxadol formulation is at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 98% d6-valent. It contains copy stones. In certain embodiments, the formulation of deuterated gaboxadol comprises in the range of about 0-60%, 60-70%, 70-80%, 80-90% or 90-100% d6-gaboxadol. In certain embodiments, the deuterated gaboxadol formulation is about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 100% d6 -Includes gaboxadol. It is observed that deuterated gaboxadol species within forms of deuterated gaboxadol are not readily distinguishable by MS or NMR analysis. As shown in Fig. 1e , d5-Gaboxadol has 6 types. They have the same weight which cannot be easily distinguished by MS. For the purposes of this specification, in certain embodiments, percentages do not necessarily specify which species of d5-gaboxadol are present in the composition, but only indicate the total amount of all species represented as peaked forms of d5-gaboxadol. do.

In a further embodiment, the synthesis is performed in Example 1B as d2-Gaboxadol 4,5,6,7-tetrahydroisooxazolo(5,4-c)pyridin-3(2H)-one-7,7 Can produce certain known species of gaboxadol, such as In this case, the specific species of d2-gaboxadol in the formulation can be known, and thus the form as well as the percentage of the specific species.

As used herein, a composition in which at least 10% of the compounds have D in one or more of R4, R4', R5, R5', R7 and R7' is a gaboxadol compound (deuterated and specific gravity) in the composition hydrogenated gaboxadol compounds), as long as at least 10% have at least one deuterium, a deuterium may be present at one or more of any indicated positions. Compositions in which at least 10% of the compounds have D in three or more of R4, R4', R5, R5', R7 and R7', wherein at least 10% of the compounds (deuterated and unhydrogenated gaboxadol compounds) are d3- It means Gaboksadol or higher. The composition may also contain d2-, d1- and unhydrogenated gaboxadol, but these are not included in the total percentages indicated.

For the avoidance of doubt, as used herein, the percentage of deuterated gaboxadol in a composition (or formulation) does not mean the total amount of deuterium relative to the total amount of gaboxadol. A 10% d6-gaboxadol composition cannot be confused with a 60% d1-gaboxadol composition by this scale since the total deuterium per unit gaboxadol is the same. Here, percentages may be used in relation to a composition to specify the percentage of a particular form of gaboxadol within the total gaboxadol (deuterated and deuterated) in the composition. As used herein, the former will be a composition of 10% d6-gaboxadol, while the latter will be a composition of 60% d1-gaboxadol.

For therapeutic use, deuterated gaboxadol is preferably stable under the conditions to which it will be exposed when administered to a patient, eg in an aqueous physiological environment, including an acidic or basic environment in the patient's body. For this reason, any proposed use of deuteration via exchangeable protons such as amines N-H, via proton-deuterium equilibrium exchange, is unlikely to be therapeutically different from non-deuterated gaboxadol, and in vivo It would not be expected to behave as a cyclic carbon deuterated gaboxadol of the present invention.

Unlike the hydrogens of amine and hydroxyl moieties, which can participate in exchange reactions, carbon backbone hydrogens are stable to exchanges even under aprotic environments and physiological conditions. Thus, the present invention contemplates the use of gaboxadol which is deuterated at the ring carbon. Deuteration of the ring carbons yields gaboxadol with 2, 4 or 6 deuterium atoms per molecule. Partial deuteration at each ring carbon yields gaboxadol with 1, 3 or 5 deuterium atoms per molecule. Various forms of deuterated gaboxadol having from 1 to 6 ring carbon bonded deuterium atoms per molecule are shown in Figures 1-2 . As discussed earlier herein, these are examples of "ring carbon deuterated gaboxadol" or simply "deuterated gaboxadol".

Here, we describe various exemplary forms of deuterated gaboxadol with reference to the ring numbering convention shown in FIG. 2 . These forms include 4,5,6,7-tetrahydroisooxazolo(5,4-c)pyridin-3(2H)-one-4,4-d ₂ ; 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3(2H)-one-5,5-d ₂ ; 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3(2H)-one-7,7-d ₂ ; 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3(2H)-one-4,4,7,7-d ₄ ; 4,5,6,7-tetrahydroisooxazolo(5,4-c)pyridin-3(2H)-one-4,4,5,5-d ₄ ; 4,5,6,7-tetrahydroisooxazolo(5,4-c)pyridin-3(2H)-one-5,5,7,7-d ₄ ; and 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3(2H)-one-4,4,5,5,7,7-d ₆ .

Other forms of deuterated gaboxadol may have an unpaired deuterium on a ring carbon such that the ring carbon has one hydrogen and one deuterium. These include d1, d3 and d5 gaboxadol, eg 4,5,6,7-tetrahydroisooxazolo(5,4-c)pyridin-3(2H)-one-4-d ₁ , 4,5 ,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3(2H)-one-5-d ₁ ; 4,5,6,7-tetrahydroisooxazolo(5,4-c)pyridin-3(2H)-one-7-d ₁ ; other d1-gaboxadol; 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3(2H)-one-4,4,5-d ₃ ; 4,5,6,7-tetrahydroisooxazolo(5,4-c)pyridin-3(2H)-one-4,4,7-d ₃ ; 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3(2H)-one-5,5,7-d ₃ ; other d3-gaboxadol; 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3(2H)-one-4,4,5,5,7-d ₅ ; 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3(2H)-one-4,5,5,7,7-d ₅ ; and 4,5,6,7-tetrahydroisooxazolo(5,4-c)pyridin-3(2H)-one-4,4,5,7,7-d ₅ . Each of the compounds named above can describe two molecules, depending on which side of the tetrahydro-pyridine ring in the molecule is the unpaired deuterium.

Here also refers to ring carbon deuterated forms of gaboxadol in an abbreviated manner as gaboxadol d2, gaboxadol d3, gaboxadol d4, gaboxadol d5 and gaboxadol d6. In some instances, d may be capitalized as D. In some examples, dashes may or may not be used. In each instance, this application refers to deuterated gaboxadol and the integer from 1 to 6 refers to the number of deuterium atoms in the gaboxadol molecule. In some examples, integers may be subscript or superscript.

Cyclic carbon deuterated gaboxadol is preferably prepared synthetically from deuterated precursors. Exemplary synthetic pathways are schematically shown, for example in FIGS. 3 and 5-11 , and synthesis is described elsewhere herein.

The synthesized form of deuterated gaboxadol has at least 25% deuteration of the synthetically targeted insertion site, more preferably at least 30%, 35%, 40%, 45%, 50%, 55%, 60% , 65%, 70%, 75%, 80% or 85%, most preferably at least 90%, 95% or 100% deuteration at the intended site.

As demonstrated elsewhere herein, mass spectrometry (MS) has determined the determination of various types of ring carbon deuterated gaboxadol in compositions of deuterated gaboxadol synthesized as described herein or by other synthetic methods. stones (d1-d6) and any non-deuterated gaboxadol. Certain types of MS, such as high-resolution MS (HRMS), will provide higher precision. Others such as electrospray ionization MS (ESI-MS) are suitable. One skilled in the art will understand how to prepare samples for MS analysis. Due to the nature of the composition of deuterated gaboxadol, the analytical chemist will want to consider certain additional steps to characterize the sample. For example, if the sample is likely to contain exchange-reacted deuterated gaboxadol, the sample may be pre-treated to remove any deuterium bound to heteroatoms in the molecule. This pre-treatment will reduce ambiguity in the results allowing a more precise assessment of the form of cyclic carbon deuterated gaboxadol in the sample.

Further, the analytical chemist will appreciate that the peaks identified by MS do not differentiate between the species of d1 to d5, but only the total amount of each form of cyclic carbon deuterated gaboxadol. In certain embodiments, the species of each form need not be distinct in order to calculate the relative proportions of the forms to each other, or to calculate the percentage of each form in a composition. In another example, the skilled analytical chemist will recognize that d6-gaboxadol and non-deuterated gaboxadol each have only one form. By MS, this form will usually show a single dominant mass peak, but no carbon-13 isotope (1.1% of naturally occurring carbon) or nitrogen-15 isotope (0.4% of naturally occurring nitrogen). Due to the incorporation, a small amount of one neutron heavier will also appear. In certain embodiments, an analytical chemist uses a minor peak one neutron heavier than d6-gaboxadol to estimate the approximate proportion of carbon-13 or nitrogen-15 isotopes in the source material for the composition of deuterated gaboxadol under investigation. Use

The cyclic carbon deuterated gaboxadol can be provided in the form of a pharmaceutically acceptable salt such as, but not limited to, an acid addition salt, zwitterion hydrate, zwitterionic anhydride, hydrochloride or hydrobromide salt, or zwitterion monohydrate. Acid addition salts include, but are not limited to, maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bis-methylenesalicylic acid, methanesulfonic acid, ethane-disulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid , malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-amino-benzoic acid, glutamic acid, benzene sulfonic acid or theophylline acetic acid addition salts as well as 8-halo theophylline, such as 8-bromo-theophylline. In other suitable embodiments, inorganic acid addition salts may be used, including but not limited to hydrochloric acid, hydrobromic acid, lithium, sulfuric acid, sulfamic acid, phosphoric acid or nitric acid addition salts. In certain embodiments, deuterated gaboxadol is provided as deuterated gaboxadol monohydrate.

In certain embodiments, base salt forms of cyclic carbon deuterated gaboxadol are prepared, wherein the base is selected from aluminum, ammonium, calcium, copper, ferric, ferrous, magnesium, manganese salts. , manganese, potassium, sodium, zinc bases, and primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, Choline, N,N-dibenzyl(ethylene)diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, Glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine , an organic or inorganic base selected from tromethamine.

Reference herein to "deuterated gaboxadol" refers to pharmaceutically acceptable salts, e.g., pharmaceutically acceptable acid addition salts, solvates or hydrates of bases or salts, as well as anhydrides, unless the context indicates otherwise. and also amorphous or crystalline forms.

In certain embodiments, the deuterated gaboxadol or pharmaceutically acceptable salt thereof is crystalline, such as a crystalline hydrochloric acid salt, a crystalline hydrobromic acid salt, or a crystalline zwitterion monohydrate. In certain embodiments, deuterated gaboxadol is provided as a crystalline monohydrate.

Uses of deuterated gaboxadol

Deuterated gaboxadol is useful in the treatment of psychiatric disorders. The present invention provides a method for treating a mental disorder comprising administering to a human patient in need thereof a therapeutically effective amount of a deuterated gaboxadol compound (eg, which may be d6-gaboxadol). provides a way In certain embodiments, a pharmaceutical composition is administered, wherein the pharmaceutical composition comprises a therapeutically effective amount of a deuterated gaboxadol compound and a pharmaceutically acceptable carrier. In certain embodiments, the mental disorder is agoraphobia, anorexia nervosa, any anxiety disorder, attention deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), binge eating disorder, bipolar disorder, borderline personality disorder, bulimia nervosa, Dementia, eating disorders, generalized anxiety disorder, major depression, obsessive-compulsive disorder (OCD), panic disorder, persistent depressive disorder (dysthymic disorder), personality disorders, post-traumatic stress disorder (PTSD), postpartum depression, schizophrenia, social anxiety disorder , or social and other specific phobias, or treatment-resistant depression (TRD). Deuterated gaboxadol can be administered to a patient alone or in combination with additional compounds to provide an additive or synergistic response in the patient.

As shown in Example 7 herein below, 6 mg/kg of deuterated gaboxadol 4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridin-3(2H)-one- 7,7-d2 (d2-gaboxadol 7,7) was surprisingly effective at equal dose ratios in several brain regions associated with cognitive processing and antidepressant drug activity, as measured in whole-brain activation studies in mice. - Deuterated induced significantly higher brain activation than gaboxadol. As shown in Example 8 herein below, d6-gaboxadol has significantly higher brain activity than non-deuterated gaboxadol at the same dose across multiple brain regions involved in cognitive processing as well as antidepressant drug activity in mice. activation, and the onset of d6-gaboxadol-induced sedation in mice was faster than that of d2-gaboxadol 7,7, whereas both d6-gaboxadol and d2-gaboxadol 7,7 The onset of sedation induced by all was faster than that of unhydrogenated gaboxadol.

Preferably, the cyclic carbon deuterated gaboxadol compound is more active in one or more regions of the brain than a non-deuterated gaboxadol, preferably about 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400%, 425%, 450%, 475% and 500% It is more active in one or more regions of the brain than non-deuterated gaboxadol administered at an equivalent dose by weight. In other words, the effective dose of cyclic carbon deuterated gaboxadol is significantly lower than the dose of non-deuterated gaboxadol required to achieve the same effect. This is sometimes referred to as a left shift dose response as described in the Examples below. As is well known in the art, the use of lower dosages of therapeutic agents, when possible, is highly desirable and sometimes medically necessary.

The various forms of deuterated gaboxadol of the present invention may be used in combinations as determined appropriate by a physician, psychiatrist or other professional caring for a patient in need of treatment. For example, an individual administration can be any of d2-gaboxadol, d4-gaboxadol or d6-gaboxadol. In addition, the combination of d2-gaboxadol, d4-gaboxadol and d6-gaboxadol can be given as individual doses or individually as multiple doses. Finally, individual administrations may include mixtures of d2-gaboxadol, d4-gaboxadol and d6-gaboxadol. Each of the foregoing combinations may include a portion of d1-gaboxadol, d3-gaboxadol, d5-gaboxadol and/or non-deuterated gaboxadol. Appropriate administration of compounds, combinations of compounds and single or multiple administrations thereof will be determined by a skilled physician, psychiatrist or other professional caring for a patient in need of treatment, taking into account the specific needs of any individual patient.

Methods, compositions and pharmaceutical compositions for the treatment of psychiatric disorders using deuterated gaboxadol or a pharmaceutically acceptable salt thereof are described herein.

The present invention provides treatment of a patient in need of treatment comprising administering deuterated gaboxadol. The treatment may be administered one or more times daily or periodically, such as every 2, 3, 4, 5, 6, 7, 8, 9 or 10 days, or about 1 to 10 days followed by a washout period in which deuterated gaboxadol is not administered. It may be intermittent or sporadic, with the first dose of deuterated gaboxadol and an optional second dose within about 12 hours.

In certain embodiments, the deuterated gaboxadol is administered once without further administration for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days. If treatment is successful, no further doses of deuterated gaboxadol need be administered until the patient experiences the unwanted symptoms again.

In certain embodiments, the present invention provides a significant difference from previously proposed treatment modalities by using lower doses of deuterated gaboxadol than non-deuterated gaboxadol. Previously proposed uses of gaboxadol that have not been clinically approved include analgesics, anxiolytics, combination anxiolytics, and escitalopram for the treatment of insomnia and the treatment of symptoms of insomnia and certain genetic developmental disorders. include antidepressants that act as add-ons to (Foster et al., 1983; Hoehn-Saric, 1983; Kasper et al., 2012; Kjaer and Nielsen, 1983; Korsgaard et al., 1982; Mohr et al. al., 1986; Mondrup and Pedersen, 1983). In certain embodiments, the present invention is used for the treatment of psychiatric disorders, such as for rapidly reducing the risk of suicide in an urgent care setting and for the rapid relief of depression, e.g., treatment-resistant depression, and/or for the delay of traditional antidepressants. For initiation of treatment of major depression to bridge the effects, deuterated gaboxadol is given.

In certain embodiments, the incidence of suicidal ideation within a population of patients suffering from acute suicidal tendencies is 10%, 20%, 30%, 40%, 50%, 60%, 70% within 24 hours of administration of deuterated gaboxadol. , reduced by 80%, 90%, 95% or 100%.

In certain embodiments, there is provided a method of treating a mental disorder comprising administering a first treatment of a single dose of deuterated gaboxadol, which preferably exhibits a higher pharmacological activity than gaboxadol, wherein A single dose results in rapid relief of the mental disorder (effective treatment).

Example 7 herein demonstrates that about 6 mg/kg of cyclic carbon deuterated gaboxadol (7,7- d2 ) is equivalent to about 10 to 20 mg/kg of non-deuterated gaboxadol in brain activation in mice. It has been demonstrated in mice that it has a negative effect. Thus, deuterated gaboxadol can have a 2- to 4-fold higher potency than undeuterated gaboxadol, and thus, any given dose of non-deuterated gaboxadol, converted from, for example, mouse doses. In terms of dose, it is envisaged that an equivalent dose of deuterated gaboxadol may be, for example, 2 to 5 times less.

In certain embodiments, the amount of mg/kg of deuterated gaboxadol to be administered daily to an adult human can be calculated using the above information and/or a formula for dose conversion based on body surface area (BSA) in an experimental animal, e.g., a mouse. It can be inferred by calculations from the dose of gaboxadol administered to and by reference to, for example, Table I.

In certain embodiments, a dose of deuterated gaboxadol refers to the amount of mg of deuterated gaboxadol administered daily to an adult human.

Table I:

Conversion of Mouse Gaboxadol Dose (mg/kg) to Human Equivalent Dose (HED) Gaboxadol (mg/kg) Based on Body Surface Area

In certain embodiments, a first dose of a pharmaceutical composition comprising deuterated gaboxadol is administered with a sustained effect for at least 3, 4, 5, 6, or 7 days after administration, also referred to as rapid relief, leads to rapid relief of mental disorders;

In certain embodiments, the method comprises administering to a patient in need thereof a first dose of a pharmaceutical composition comprising from about 1 mg to about 300 mg of deuterated gaboxadol or a pharmaceutically acceptable salt thereof. wherein the first dose provides an improvement in the patient for at least 3, 4, 5, 6, or 7 days after administration to the patient. In certain embodiments, no form of gaboxadol is administered to the patient for more than 3, 4, 5, 6, or 7 days after the first administration.

Certain embodiments described herein provide that a pharmaceutical composition comprising deuterated gaboxadol is administered to a patient in need thereof. Deuterated gaboxadol can be provided as a pharmaceutically acceptable salt thereof. Examples of pharmaceutically acceptable salts are provided elsewhere herein.

In certain embodiments, deuterated gaboxadol is provided as deuterated gaboxadol monohydrate. One skilled in the art will readily appreciate that the amount of active ingredient in the pharmaceutical composition can be adjusted depending on the form of deuterated gaboxadol provided. For example, a pharmaceutical composition comprising 5.0, 10.0, 15.0, 33.0, 50.0 or 150.0 mg of deuterated gaboxadol is equivalent to 5.6, 11.3, 16.9, 37, 56 or 169 mg of deuterated gaboxadol monohydrate, respectively. respond

In certain embodiments, the deuterated gaboxadol is crystalline.

Exemplary Doses of Deuterated Gaboxadol

In certain embodiments, administering to a patient in need thereof a first dose of a pharmaceutical composition comprising from about 1 mg to about 300 mg of deuterated gaboxadol or a pharmaceutically acceptable salt thereof There is provided a method of treating a mental disorder comprising a.

In certain embodiments, the deuterated gaboxadol is 1 mg to 150 mg, about 5 mg to about 20 mg, about 33 mg to about 75 mg, about 33 mg to about 100 mg, about 50 mg to 100 mg, or about An amount of deuterated gaboxadol or a pharmaceutically acceptable salt thereof ranging from 33 mg to about 150 mg is present in the pharmaceutical composition. In certain embodiments, the pharmaceutical composition is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25 , 30, 33, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145 , 150, 175, 200, 250, or 300 mg of deuterated gaboxadol or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, when deuterated gaboxadol is used as a single or first-line agent, the first dose is a single dose ranging from about 1 mg to about 300 mg.

In certain embodiments, when deuterated gaboxadol is used as a single or first-line agent, the first administration is about 1 mg to about 20 mg, about 5 mg to about 10 mg, about 10 mg to about 10 mg of deuterated gaboxadol. About 30 mg, about 25 mg to about 50 mg, about 33 mg to about 150 mg, about 40 mg to about 150 mg. 50 mg to about 150 mg, about 50 mg to about 100 mg, about 60 mg to about 300 mg, about 70 mg to about 300 mg, about 80 mg to about 300 mg, about 90 mg to about 300 mg, about 100 mg to about 300 mg, about 110 mg to about 300 mg, about 120 mg to about 300 mg, about 130 mg to about 300 mg, about 140 mg to about 300 mg, about 150 mg to about 300 mg, about 200 mg to about 300 mg, or about 250 mg to about 300 mg in a single dose.

In certain embodiments, the dose of deuterated gaboxadol administered is about 50 mg, 75 mg or 100 mg.

In certain embodiments, when the first administration of deuterated gaboxadol is in combination with another agent, such as ketamine or another second pharmaceutical agent, the deuterated gaboxadol is from about 1 mg to about 10 mg, e.g. Dosages as low as, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 mg may be used in certain embodiments.

In certain embodiments, when the first administration of deuterated gaboxadol is in combination with another agent, such as lithium or another second pharmaceutical agent, in certain embodiments the deuterated gaboxadol is from about 1 mg to about 20 mg , for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg. there is.

In certain embodiments, the plasma Tmax of deuterated gaboxadol is achieved within 45 minutes after administration.

In certain embodiments, the dosage of deuterated gaboxadol or a pharmaceutically acceptable salt thereof is about 20 mg, about 19 mg, about 18 mg, about 17 mg, about 16 mg, about 15 mg, about 14 mg, About 13 mg, about 12 mg, about 11 mg, about 10 mg, about 9 mg, about 8 mg, about 7 mg, about 6 mg, about 5 mg, about 4 mg, about 3 mg, about 2 mg, about 1 mg or less.

It is meant that a dosage of a salt or hydrate of deuterated gaboxadol that is equivalent on a molar basis to the amount of deuterated gaboxadol in any given dosage recited above is within the scope of the present invention.

In certain embodiments, the deuterated gaboxadol is administered daily (eg, once daily), or optionally more than once daily, at a dosage determined by the treating physician. In an alternative embodiment, it may be administered intermittently, such as regularly in some phases of treatment and irregularly in other phases, such as 48 hours, 3 4, 5, 6, 7, 8, 9 or 10 allow for a washout period between dosing of days. In certain embodiments, the deuterated gaboxadol is administered once without further administration for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days.

dosage form

In certain embodiments, the present invention contemplates administration of a pharmaceutical composition comprising deuterated gaboxadol or a pharmaceutically acceptable salt thereof, optionally designed for rapid onset of therapeutic effect. A wide variety of dosage forms may be used, including those previously described in the literature. Preferred dosage forms are suitable for oral or intranasal administration.

In certain embodiments, the pharmaceutical compositions herein are provided in an immediate release or standard release profile. The pharmaceutical composition may further include a pharmaceutically acceptable “carrier”. In certain embodiments, a pharmaceutically acceptable carrier can be or include one or more of a diluent, binder, lubricant disintegrant, filler, and coating composition. In certain embodiments, unit dosage forms (UDFs) are provided. In a preferred embodiment, the pharmaceutical composition or UDF is a pill, tablet, capsule, film or wafer, any of which is optionally orally disintegrating or a lollipop, lozenge, oil, tincture or syrup. can The formulation process can be adjusted accordingly. Pills and tablets can be prepared from solid dosage forms. Syrups, oils and tinctures are liquid formulations. In certain embodiments, an orally disintegrating film, wafer, tablet or lollipop or lozenge provides the UDF in oral form, wherein the active ingredient is at least partially absorbed directly in the oral cavity. Capsules may be used, containing solid formulations or liquid formulations (eg, powders or particles in hard-gels, or oily formulations in soft-gels). In certain embodiments, oily formulations with little or no water are used, which are typically easily encapsulated. Oil-in-water formulations may be used including microemulsions, liposomes, nanoemulsions or other forms known in the art.

Tablets may be prepared by mixing the active ingredient with common adjuvants and/or diluents and then compressing the mixture in a convenient tableting machine. Examples of adjuvants or diluents include corn starch, lactose, talc, magnesium stearate, gelatin, lactose, gum, and the like. Any other pharmaceutically acceptable adjuvants or additives such as colorants, fragrances, preservatives and the like may be used provided they are compatible with the active ingredient.

A wide variety of technologies are available for buccal or sublingual dosage forms such as orally disintegrating thin films, wafers or tablets, or lollipops and/or lozenges. Sublingual tablets, wafers, films and strips are designed to disintegrate quickly (5-15 seconds), allowing rapid access to oral capillaries and avoiding the adverse environment of the gastrointestinal tract. Lollipops and lozenges provide a combination of oral and gastric administration. This technology is widely used with therapeutics where rapid onset is desired. (See Lamey and Lewis "Buccal and Sublingual Delivery of Drugs" Ch 2 in "Routes of Drug Administration" Ed. Florence and Salole (Butterworth-Heinemann)). In certain embodiments, an orally disintegrating tablet ODT is used (see Lamey and Lewis (1990)).

Prior art formulations of non-deuterated gaboxadol or pharmaceutically acceptable salts thereof that can be used for deuterated gaboxadol are disclosed in the following patent publications, the contents of which are hereby incorporated in their entirety: Included as: WO2018144827, US20110082171, US20090048288, WO2006118897, WO2006102093, GB2410434, US20050137222, WO2002094225, WO2001022941. Deuterated gaboxadol can be administered in oral dosage form.

Treatment and its therapeutic effect

In one embodiment, the present invention relates to treatment of a mental disorder comprising administering to a patient a pharmaceutical composition comprising deuterated gaboxadol or a pharmaceutically acceptable thereof, for example, if the patient is diagnosed as having a mental disorder. Consider treating psychiatric disorders in patients with In certain embodiments, the patient is in an urgent care facility or clinic where the diagnosis was made. The method of the present invention comprises administering a therapeutic dose with patient consent immediately after diagnosis.

In certain embodiments, the invention also relates to traditional antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tetra Cyclic antidepressants (TeCA), monoamine oxidase inhibitors (MAOIs) or noradrenaline and certain serotoninergic antidepressants (NASSA) require rapid antidepressant relief before the typical time delay onset of clinical efficacy Treatment with a pharmaceutical composition comprising deuterated gaboxadol or a pharmaceutically acceptable salt thereof is considered upon initial diagnosis of depression in a patient. Typically, the patient is in an urgent care facility or clinic where the diagnosis was made.

In certain embodiments, the present invention also provides treatment-resistant depression in patients in need of rapid relief where treatment with conventional antidepressants has failed to induce clinical relief or provide sustained relief after an initial period of successful treatment. Treatment with a pharmaceutical composition comprising digestive gaboxadol, or a pharmaceutically acceptable salt thereof, is contemplated. Typically, the patient is in an urgent care facility or clinic where the diagnosis was made. In certain embodiments, the methods of the present invention contemplate administration of the first dose immediately after diagnosis and with the consent of the patient. In certain embodiments, the patient has received or is recommended for electroconvulsive therapy.

A preferred biomarker measure of rapid onset is the measurement of brain activity by electroencephalography (EEG). EEG is a measure of neural activity well known to those skilled in the art. Standard techniques and instruments are widely available. Low-frequency emissions are measured over the spectral range of typically 0.2-35 Hz at various locations on the patient's head. Power spectra are evaluated at each wavelength (or across a range of wavelengths) to observe and detect neurological activity. EEG is described in Dijk et al. (2010) J. Psychopharmacology. 24(11) 1613-1618] can be used in the context of measuring neural responses to drugs such as gaboxadol. See also Lundahl et al. (2011) J Psychopharmacol 26: 1081.

Magnetoencephalography is an alternative neuroimaging technique with high temporal resolution and moderately good spatial resolution that allows direct measurement of magnetic fields generated by synchronized ionic neurocurrents in the brain. MEG (Pharmaco-MEG), when combined with pharmacological interventions, is a powerful tool for measuring the effects of experimental modulation of neurotransmission in the living human brain in both patients and healthy controls (Muthukumaraswamy, 2014). Compared to EEG, it can provide superior spatial resolution and reduced contamination of brain signals by physiological artifacts such as blinks and muscle potentials. See Nutt et al. Neuropharmacology 88 (2015) 155-163].

In certain embodiments, the present invention provides that administration of a pharmaceutical composition comprising deuterated gaboxadol or a pharmaceutically acceptable salt thereof demonstrates a rapid onset of a therapeutic effect, e.g., a rapid reduction in symptoms of a psychiatric disorder. Consider inducing A biomarker measure of rapid onset can be obtained by EEG. An increase in EE power density of about 30% or more across the spectrum ranging from 0.25 Hz-8.0 Hz within about 180 minutes of administration indicates a rapid onset of effect. Preferably, the patient will report a power density increase of about 50% or greater over this range. More preferably, the patient will report a power density increase of about 50% or greater over the 4.75-8.0 Hz range. EEG power density increases have been described by Dijk (2010) and Lundahl (2011) upon administration of gaboxadol, in the context of other disease indications. In certain embodiments, these techniques are used with deuterated gaboxadol in the indications disclosed herein.

Alternatively, MEG can be used as a biomarker to monitor the rapid onset of therapeutic effects of deuterated gaboxadol or gaboxadol administration. In the context of other treatment indications, Nutt et al (2015) observed that administration of gaboxadol led to whole-head MEG planar durometer increases in combined delta, theta and alpha activity at 160 minutes after first treatment did In certain embodiments, the treatment methods of the present invention achieve an increase of +3 or greater within about 180 minutes of the first treatment.

In certain embodiments, the method of treatment of the present invention provides that administration of a pharmaceutical composition comprising deuterated gaboxadol relieves symptoms of a psychiatric disorder for about 3, 4, 5, 6, 7, 8, 9, 10 or more days after administration. achieve a lasting effect in terms of reducing

Without wishing to be bound by theory, it is hereinafter believed that administration of deuterated gaboxadol induces a chemical form of brain activation via subunit-containing GABA _A receptors that can be interpreted as physiological effects comparable to electroconvulsive therapy (ECT). Considered based on the embodiment of. One skilled in the art may choose less frequent dosing, such as 2, 3, 4, 5, 6 or 7 days after the first treatment, but according to one aspect of the invention, the effect of administration is optionally deuterated daily after the first administration. It can be improved by maintaining administration of gaboxadol. Accordingly, a method for treating a mental disorder is provided comprising the repeated steps of daily administration of deuterated gaboxadol to a patient in need of treatment for a mental disorder. In certain alternative embodiments of the method of treating a mental disorder in a patient, the less frequent than daily administration is administration of the deuterated gaboxadol every 2, 3, 4, 5, 6 or 7 days after the first administration. It is used like an iterative step to do. In certain embodiments of one form of therapy, no further administration is administered until the patient's symptoms indicate that further treatment will be beneficial, which may occur 3, 4, 5, 6 or more days after said first administration, or longer. It may not happen at all during the period. In other words, in certain embodiments, additional administration with deuterated gaboxadol may be optionally avoided within a 3-day period after completion of the first administration, for example, if such additional administration reduces the effectiveness of the treatment. . In certain embodiments, if a period of 3 days or more is selected after the first administration, that period may be considered a "washout" period. In certain embodiments, the 3-day treatment-free period may be extended to 4, 5, or 6 days or longer if reduced symptoms of the psychiatric disorder are maintained. It is further understood that if symptoms of the psychiatric disorder recur more than 3 days after the first administration, subsequent treatment with deuterated gaboxadol or a pharmaceutically acceptable salt thereof may be administered. In some cases, 4-day, 5-day, 6-day or weekly administration, each eg for "intermittent dosing", will be indicated for the patient. In certain embodiments, administration, in each case, is considered a continuation of treatment of a disorder according to the present invention.

In a further embodiment, the treatment of a psychiatric disorder with deuterated gaboxadol, or a pharmaceutically acceptable salt thereof, comprises initial administration of a pharmaceutical composition comprising deuterated gaboxadol, or a pharmaceutically acceptable salt thereof, and optionally, a second administration of a pharmaceutical composition comprising deuterated gaboxadol, or a pharmaceutically acceptable salt thereof, within about 12 hours immediately after the initial administration. In certain embodiments, the total amount of the first and second administrations does not exceed a total of 200 mg.

The deuterated gaboxadol of the present invention may be used in combination with gaboxadol (ie, non-deuterated gaboxadol). In certain embodiments of the method of treatment of the present invention where two administrations are performed, either form may be the first or second administration.

The various forms of deuterated gaboxadol of the present invention may be used in combinations as determined appropriate by a physician, psychiatrist or other professional caring for a patient in need of treatment. For example, an individual administration can be any of d2-gaboxadol, d4-gaboxadol or d6-gaboxadol. Additionally, the combination of d2-gaboxadol, d4-gaboxadol and d6-gaboxadol, or a combination of any two of the foregoing, may be given as individual doses or individually as multiple doses. Alternatively, individual administrations may include a mixture of d2-gaboxadol, d4-gaboxadol and d6-gaboxadol. Each of the foregoing combinations may include a portion of d1-gaboxadol, d3-gaboxadol, d5-gaboxadol and/or non-deuterated gaboxadol. Appropriate administration of compounds, combinations of compounds and single or multiple administrations thereof may be determined by a skilled physician, psychiatrist or other professional caring for a patient in need of treatment, taking into account the specific needs of any individual patient. .

In certain embodiments, the decision regarding the optional second administration is based on a metric of patient response to the first administration. Any response of the patient can be used to make a decision, including any changes in behavior or physiological or biological markers of the response. In certain embodiments, an insufficient response to a first administration precedes performance of a second administration.

The preferred patient response for determining the sufficiency of a response is based on measuring the patient's neurological response according to EEG or MEG. In certain embodiments, an “insufficient response” is an increase in EEG power density of less than 50% or optionally less than 30% across the spectrum 0.25-8.0 Hz at 160 minutes after first administration. In another specific embodiment, an “insufficient response” is an increase in EEG power density of less than 50% or optionally less than 30% across the spectrum 4.75-8.0 Hz at 160 minutes after first administration.

In certain embodiments, an inadequate response to a first dose is a whole-head MEG planometry increase of less than +3 in combined delta, theta, and alpha activity at 160 minutes after the first dose.

In certain embodiments, an insufficient response is persistence of observable symptoms of a mental disorder, such as suicidal ideation, acute suicidal tendencies, risk of self-harm, and/or treatment-resistant depression.

In certain embodiments, a method of treating a mental disorder comprising administering a pharmaceutical composition comprising deuterated gaboxadol comprises a second administration within up to about 12 hours of the first administration to achieve a desired therapeutic effect. can do. Preferably the second administration will follow immediately after confirmation of an insufficient response by EEG or MEG at the 160 minute time point. The second administration may be delayed for various patient management reasons, but is preferably within about 12 hours of the first administration.

In certain embodiments, the washout period between the first treatment and the subsequent treatment (in certain embodiments, at least 48 hours and optionally at least 3 days after the first treatment) reflects the neurological effects of deuterated gaboxadol treatment and , which corresponds to observations of a ketamine clinical trial of extended duration of 7 days or longer, where the first treatment is, but is not limited to, suicidal ideation, recurrent death, as described in U.S. Patent No. 9,359,220, which is incorporated herein by reference in its entirety. It is sufficient to relieve symptoms of mental disorders such as thoughts about suicide, suicidal behavior, and suicide attempts. In certain embodiments, this also corresponds to a period of reduction in suicidal ideation observed in certain patients receiving electroconvulsive therapy. Without being bound by theory, if administration of the therapeutic agent instead occurred during a washout period, for example, administration of a maintenance dose of the therapeutic agent or additional electroconvulsive therapy, neurological recovery from the electrical or chemical shock of the first treatment It is believed that it can be counterproductive due to re-stimulation of neurological areas that would interfere with the desired pattern of sleep.

Oral administration may use any orally acceptable form including, but not limited to, pills, tablets, capsules, syrups, and the like. Such forms can be prepared according to techniques well known to those skilled in the art.

A particularly preferred form for rapid onset is an orally disintegrating dosage form (ODDF), which provides immediate release enhancing oral absorption of the drug in the oral cavity of the patient. ODDF is a solid dosage form containing a medicinal substance or active ingredient that rapidly disintegrates, usually within seconds, when placed on the tongue. The disintegration time of ODDF generally ranges from 1 or 2 seconds to about 1 minute. ODDF is designed to rapidly disintegrate or dissolve upon contact with saliva. This mode of administration may in fact be beneficial to persons who may have problems swallowing tablets, as is common in psychiatric conditions.

In certain embodiments, the pharmaceutical compositions herein provide immediate release of deuterated gaboxadol or a pharmaceutically acceptable salt thereof, eg, as described in the Revision Bulletin Official dated Aug. 1, 2008, section When administered orally, based on the United States Pharmacopeia (USP) disintegration test method according to 701, less than 1 minute, less than 55 seconds, less than 50 seconds, less than 45 seconds, less than 40 seconds, less than 35 seconds, less than 30 seconds, 25 Disintegrates in less than seconds, less than 20 seconds, less than 15 seconds, less than 10 seconds or less than 5 seconds.

In a preferred embodiment, ODDF results in pharmacokinetic properties comprising a Tmax of 20 minutes or less. In certain embodiments, the pharmaceutical composition herein provides a Tmax of 20 minutes or less, a Tmax of 19 minutes or less, a Tmax of 18 minutes or less, a Tmax of 17 minutes or less, a Tmax of 16 minutes or less, a Tmax of 15 minutes or less, a Tmax of 14 minutes or less Tmax, Tmax of 13 minutes or less, Tmax of 12 minutes or less, Tmax of 11 minutes or less, Tmax of 10 minutes or less, Tmax of 9 minutes or less, Tmax of 8 minutes or less, Tmax of 7 minutes or less, Tmax of 6 minutes or less, or a Tmax of 5 minutes or less. Such a pharmaceutical composition may be an ODDF such as an orally disintegrating tablet (ODT).

ODT is a solid dosage form, for example a tablet, film or wafer containing a drug substance or active ingredient, which disintegrates rapidly when placed on the tongue, generally within seconds. The disintegration time of ODT is generally in the range of a few seconds to about 1 minute. ODT is designed to disintegrate or dissolve rapidly upon contact with saliva, thereby eliminating the need to chew the tablet, swallow the tablet whole, or consume the tablet with liquid. Like ODDF in general, this mode of administration can be beneficial for those in need of rapid onset of treatment.

In certain embodiments, the rapid dissolution properties of ODT require rapid water penetration into the tablet matrix. This can be achieved by maximizing the porous structure of the tablet, incorporating suitable disintegrants and using highly water soluble excipients in the formulation. Excipients used in ODTs typically contain at least one superdisintegrant (which may have mechanisms of wicking, swelling, or both), diluents, lubricants, and optionally swelling agents, sweeteners, and flavors. See, eg, Nagar et al., Journal of Applied Pharmaceutical Science, 2011; 01(04):35-45]. Superdisintegrants are classified as synthetic, natural and co-processed. In this regard, synthetic superdisintegrants are exemplified by sodium starch glycolate, croscarmellose sodium, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, partially pregelatinized starch, cross-linked alginic acid or modified resins. It can be. Natural superdisintegrants such as processed mucus and gum are obtained from plants, Lepidium sativum seed mucus, banana powder, gellan gum, locust bean gum, xanthan gum, guar gum, gum karaya, cassia cassia fistula seed gum, Mangifera indica gum, carrageenan, agar from Gelidium amansii or other red algae, soybean polysaccharide or chitosan. Diluents that may be used include, for example, mannitol, sorbitol, xylitol, calcium carbonate, magnesium carbonate, calcium sulfate, magnesium trisilicate and the like. Lubricants that may be used include, for example, magnesium stearate and the like. A person skilled in the art is familiar with ODT manufacturing techniques. Other ODDFs that may be used include rapid dissolving films, which are thin oral strips that release rapidly after oral administration of a drug such as deuterated gaboxadol or a pharmaceutically acceptable salt thereof. The film is placed on the patient's tongue or any other mucosal surface and, upon immediate moistening with saliva, the film rapidly hydrates and dissolves to release the drug. See, eg, Chaturvedi et al., Curr Drug Deliv. July 2011; 8(4):373-80]. In certain embodiments, a fast cap is used. FastCap is a rapidly disintegrating drug delivery system based on a gelatin capsule. In contrast to conventional hard gelatin capsules, Fastcaps consist of low bloom strength gelation and various additives to improve the mechanical and dissolution properties of the capsule shell. See, eg, Ciper and Bodmeier, Int J Pharm. 2005 Oct. 13; 303(1-2):62-71].

In certain embodiments, freeze dried (lyophilized) wafers are used. Freeze-dried (lyophilized) wafers rapidly disintegrate the thin drug-containing matrix. The wafer or film rapidly disintegrates in the oral cavity and releases the drug which dissolves or disperses in saliva. For example, [Boateng et al., Int J Pharm. 2010 Apr. 15; 389(1-2):24-31]. One skilled in the art is familiar with the various techniques used to make ODDF, such as freeze drying, spray drying, phase transfer processing, melt granulation, sublimation, bulk extrusion, cotton candy processing, direct compression, and the like. See, for example, [Nagar et al.] above.

Upon administration, ODDF containing deuterated gaboxadol or a pharmaceutically acceptable salt thereof rapidly disintegrates to release a drug that is dissolved or dispersed in saliva. Drugs can be absorbed from the oral cavity, eg sublingually, orally, pharynx and esophagus, or from other parts of the gastrointestinal tract as saliva moves down. In such cases, the bioavailability can be significantly greater than that observed from conventional tablet dosage forms that travel to the stomach or intestine from which the drug can be released.

The intranasal form enhances rapid absorption of deuterated gaboxadol through the nasal and pulmonary systems. Intranasal formulations of therapeutic agents are well known and one skilled in the art can adapt deuterated gaboxadol to this format. Design choices depend on whether the product is a solution or suspension. Important parameters include pH and buffer selection, osmotic pressure, viscosity, excipient selection, and selection of penetration enhancers or other ingredients to enhance residence time in the nasal cavity. (See DPT Laboratories Ltd publications at www.dptlabs.com).

In certain embodiments, a preferred goal of the present invention is to rapidly achieve blood levels that achieve GABAA receptor saturation in the brain. The GABAA receptor saturation level of non-deuterated gaboxadol is a blood level of greater than 900 ng/ml. Using deuterated gaboxadol, one skilled in the art can calculate brain GABAA receptor saturation levels, Cmax, Tmax and AUC at different time points. For comparison, non-deuterated gaboxadol has a GABAA receptor saturation level in the brain of about 900 mg/ml, a dose of 20 mg has a Cmax of 900ng/ml, and a plasma Tmax of 1 in 90 Achieved within treatment and AUC0-∞ is about 900 ng*hr/ml.

In certain embodiments of the methods of the invention involving two administrations of deuterated gaboxadol (eg, within the first about 12 hours), different routes of administration of deuterated gaboxadol may be used. For example, if the first administration is oral, the second administration is intranasal administration and vice versa. Alternatively, both administrations may be by the same route of administration.

combination therapy

In certain embodiments, a pharmaceutical composition comprising deuterated gaboxadol or a pharmaceutically acceptable salt thereof, and lithium, ketamine, SAGE-217, allopregnanolone ganaxolone, alphadolone, alpaxolone, hydroxydione, Minaxolone, pregnanolone, lenolone, pregnanc neurosteroids, AV-101 (L-4-chlorokynurenine), rapastinel (GLYX-13), MGS0039, LY-341,495, MK-801 (dizocilpine) , Ro 25-6981, lislenemdaz (CERC-301, MK-0657), afimostinel (NRX-1074), ranisemin (AZD6765), traxoprodil (CP-101606), (2R,6R) -hydroxynorketamine, deagglomerator (INN) (RG1578, RO4995819), memantine, tiagabine, gaboxadol, clozapine, [2-amino-4-(2,4,6-trimethylbenzylamino)-phenyl] - a second comprising an active agent selected from the group consisting of carbamic acid ethyl ester (AA29504), AXS-05 (a fixed combination of dextromethorphan and bupropion) and pharmaceutically acceptable salts of any of the foregoing Provided herein is a method of treating a mental disorder comprising administering to a patient in need thereof a different pharmaceutical composition.

In certain embodiments, provided herein are methods of treating a mental disorder comprising administering to a patient in need thereof a pharmaceutical composition comprising deuterated gaboxadol or a pharmaceutically acceptable salt thereof. wherein the second pharmaceutical composition comprising the second active agent is also optionally administered concurrently with the administration of the deuterated gaboxadol according to a prescribed schedule and dosage, which may be timed.

In certain embodiments, the deuterated gaboxadol and the second active agent (of the second pharmaceutical composition) may be provided in a combined dosage form, such as a fixed dosage combination, when co-administration is to be performed.

Combinations of the present invention may provide additive and/or synergistic effects. In certain embodiments, administration of a first pharmaceutical composition comprising deuterated gaboxadol and a second pharmaceutical composition comprising a second active agent provides a synergistic effect of ameliorating at least one symptom of a mental disorder. In a preferred embodiment, the combination therapy demonstrates a synergistic effect and employs a dosage of deuterated gaboxadol and a dosage of an active agent of the second pharmaceutical composition, wherein either the deuterated gaboxadol or the second active agent or both, individually given in dosages known to be below the threshold for therapeutic effect. In certain embodiments, the present invention contemplates combination therapy, wherein the amount of deuterated gaboxadol administered is no more than 30 mg, 25 mg, 20 mg, 15 mg, 12 mg, 10 mg, 6 mg, 5 mg. In certain embodiments, the second pharmaceutical composition comprises ketamine, and the amount of ketamine may be up to about 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 mg. In another embodiment, the second pharmaceutical composition comprises lithium.

lithium

It will be appreciated that references to "lithium" herein will apply to any lithium-containing compound, including lithium salts such as lithium carbonate, co-crystals, as well as synthetic lithium drugs such as isotopically-modified lithium compounds.

lithium salt

The most common lithium-containing compound for the treatment of psychiatric disorders is naturally occurring lithium carbonate (Li ₂ CO ₃ ). A lithium carbonate molecule consists of a central carbon atom bonded to an oxygen ion and two oxygen ions each bonded to a lithium ion. The electronic valence of constituent atoms dictates both the molecular structure and the chemical and biochemical reactions of the molecule. The molecular weight of Li is 6.94 g/mol, the molecular weight of Li ₂ CO _{3 is} 73.89 g/mol, and the mass of lithium ion (Li ₊ ) in the amount of lithium carbonate is 18.79% and same.

In certain embodiments, other salt forms that can serve as a source of lithium include, but are not limited to, lithium benzoate, lithium bromide, lithium fluoride, lithium cacodylate, lithium caffeine sulfonate, lithium chloride, lithium orotate, Lithium citrate, lithium dithiosalicylate, lithium formate, lithium gaboxadolate, lithium gaboxadolate, lithium gaboxadolinate, lithium glycerophosphate, lithium iodate, lithium lactate and lithium salicylate include Lithium citrate (Li ₃ C ₆ H ₅ O ₇ ) has been approved by the FDA for the treatment of manic and bipolar disorder and is available orally in the form of capsules, syrups and tablets. Lithium orotate (LiC ₅ H ₃ N ₂ O ₄ ) and some other lithium compounds are commercially available without prescription as vitamins.

In certain embodiments, the source of lithium comprises a lithium deuterated gaboxadol salt.

In certain embodiments, a composition of a lithium salt, preferably an organic anion salt of lithium, and a complementary neutral organic compound are combined in a stoichiometric ratio. In certain embodiments, the co-crystal thus formed has the formula LiX.aM, where X is, for example, a salicylate or lactate, M is a neutral organic molecule, and a is from 0.5 to 4. In certain variations of the invention, the lithium salicylate or lithium lactate has a molar ratio to organic molecules of 1:1 or 1:2. Optionally, the organic molecule is an amino acid, synthetic amino acid, xanthine, polyphenol or sugar. In general, organic anionic lithium ion co-crystal compositions are prepared by combining a lithium salt and a complementary organic compound (i.e., co-crystal precursor) in a solvent and promoting crystallization using commonly used methods, such as evaporating the solvent or It can be prepared by cooling to form a co-crystal.

Examples of amino acids or synthetic amino acids that may be used include alanine, arginine, asparagine, aspartic acid, cysteine, isoleucine, glutamic acid, glutamine, glycine, histidine, leucine, lysine, methionine, phenylalanine, proline, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, nicotinic acid and valine. As a further example, the amino acid is an L-amino acid such as L-phenylalanine, L-leucine or L-tyrosine. In an alternative embodiment, the amino acid is a D-amino acid, such as D-phenylalanine, D-leucine or D-tyrosine. In an alternative embodiment, the co-crystal precursor comprises non-proteinogenic amino acids. Synthetic amino acids are alkyl, substituted alkyl, cycloalkyl, heterocyclic, substituted heterocyclic, arylalkyl, aryl, heteroaryl, heteroarylalkyl, and carboxyl, amine, hydroxyl, phenol, carbonyl or thiol functional groups. and naturally occurring side chain functional groups or synthetic side chain functional groups that modify or extend natural amino acids with similar moieties as frameworks; Exemplary synthetic amino acids include β-amino acids and homo or β-analogs of natural (standard) amino acids. Other exemplary amino acids include pyrrolysine, betaine, and carnitine.

Examples of xanthines are caffeine, paraxanthine, theophylline and threobromine.

Examples of polyphenols can be classified into the following categories: (1) phenolic acids, (2) flavonoids, (3) stilbenoids; (4) tannins, (5) monophenols such as hydroxytyrosol or p-tyrosol, (6) capsacin and other capsaicinoids, and (7) curcumin. Phenolic acids include, for example (a) hydroxycinnamic acids, such as p-coumaric acid, caffeic acid and ferulic acid; (b) hydroxybenzoic acids such as p-hydroxybenzoic acid, gallic acid and ellagic acid; and (c) rosmarinic acid.

In certain embodiments, the flavonoid may be resveratrol, epigallocatechin-3-gallate (EGCG), quercetin, ferulic acid, ellagic acid, hesperethene, and protocatechuic acid.

In certain embodiments where the organic molecule is a sugar, the sugar may include monosaccharides and disaccharides. For example, the sugar can be fructose, galactose, glucose, lactitol, lactose, maltitol, maltose, mannitol, melezitose, myoinositol, palatinite, raffinose, stachyose, sucrose, trehalose or xylitol .

In certain embodiments, the composition optionally contains vitamin B2 (riboflavin), glucosamine HCl, chlorogenic acid, lipoic acid, catechin hydrate, creatine, acetyl-L-carnitine HCl, vitamin B6, pyridoxine, caffeic acid, naringenin, vitamin B1 ( Thiamine HCl), baicalein, luteolin, hesperedin, rosmarinic acid, epicatechin gallate, epigallocatechin, vitamin B9 (folic acid), genistein, methylvanillin, ethylvanillin, silibinin, diazane, melatonin, rutin hydrate, Vitamin A, Retinol, Vitamin D2 (Ergocalciferol), Vitamin E (Tocopherol), Diosmin, Menadione (K3), Vitamin D3 (Caholecalciferol), Phloretin, Indole-3-Carbinol, Blood Cetin, glycitein, chrysin, gallocatechin, vitamin B4 (adenine), vitamin B5 (pantothenic acid), vitamin B7 (biotin), theobromine, resveratrol, epigallocatechin-3-gallate (EGCG), quercetin, ferrul It includes at least one nutritional supplement selected from the group consisting of acid, ellagic acid, hesperethene and protocatechuic acid. As a further example, in this embodiment, the nutritional supplement is vitamin B2 (riboflavin), glucosamine HCl, chlorogenic acid, lipoic acid, catechin hydrate, creatine, acetyl-L-carnitine HCl, vitamin B6, pyridoxine, caffeic acid, naringenin, vitamins B1 (thiamin HCl), baicalein, luteolin, hesperedin, rosmarinic acid, epicatechin gallate, epigallocatechin, vitamin B9 (folic acid), genistein, methylvanillin, ethylvanillin, silibinin, diazane, melatonin, rutin Hydrate, Vitamin A, Retinol, Vitamin D2 (Ergocalciferol), Vitamin E (Tocopherol), Diosmin, Menadione (K3), Vitamin D3 (Caholecalciferol), Phloretin, Indole-3-Carbinol , fisetin, glycitein, chrysine, gallocatechin, vitamin B4 (adenine), vitamin B5 (pantothenic acid), vitamin B7 (biotin), theobromine, quercetin, ferulic acid, ellagic acid, hesperethene and protocatechuic acid. It may be selected from the group consisting of

In certain embodiments, a lithium salt and a complementary neutral organic compound are combined in an aqueous system. In certain embodiments, the lithium salt and complementary neutral organic compound are soluble in polar organic solvents such as acetone, acetonitrile, DMSO and alcohols.

In certain embodiments, an organic anionic lithium ion co-crystal composition comprises combining a lithium-containing compound, an organic acid, and a complementary neutral organic compound in a solvent, such as water, and evaporating or cooling the solvent using commonly used methods. Likewise, it can be prepared by accelerating crystallization.

Compositions and methods for preparing and administering lithium salts and/or co-crystal compounds are known in the art and are described, for example, in US Pat. No. 9,744,189, the contents of which are incorporated herein by reference in their entirety.

Isotopically-modified lithium compounds

Many atoms fall into several stable isotopes, distinguished by the number of neutrons in their nuclei. Lithium has two stable isotopes: lithium-7 with 4 neutrons and lithium-6 with 3 neutrons. In nature, 92.5% of lithium atoms are lithium-7, while lithium-6 makes up the remaining 7.5%. As a rule, biology is insensitive to different atomic isotopes. However, a 1986 experiment showed that lithium-7-treated rat mothers ignored their pups and cared for them sparingly, whereas lithium-6-treated mothers were more alert, groomed, and cared for their pups more than regular mothers. reported frequent care (Sechzer et al., 1986). Thus, synthetic lithium-6 purified compounds consisting primarily of lithium-6 (>95% of the total lithium) are currently available with all natural lithium-isotope enrichment concentrations (i.e., 92.5% lithium-7 and only 7.3% lithium-6). It may be effective in treating mental conditions with reduced levels of arousal, such as chronic and major depression, as well as disorders not well treated with lithium pharmaceuticals. Since all naturally occurring lithium (eg, as mined from dry lake beds) contains lithium isotopes in natural abundance, lithium-6 purification requires synthetic means.

In naturally occurring lithium compounds such as lithium carbonate, the concentrations of lithium-7 and lithium-6 atoms match the natural proportions - 92.5% lithium-7 and 7.5% lithium-6. However, this concentration ratio may be modified by synthetic means, and the synthetic isotopically-modified lithium compound may exhibit various properties, including resistance to existing agents or resistance to combination with deuterium gaboxadol as described herein. It can be used to treat psychiatric disorders and conditions.

Li-6-purifying compounds:

A purified Li-6 compound can be any lithium containing compound having lithium-6 present in an amount of at least 95% of the total lithium (ie, lithium-6 and lithium-7) in the compound. The 95% threshold is well above the 7.5% natural abundance of lithium-6 occurring in (unsynthesized) lithium pharmaceuticals and is close to the ideal limit for lithium compounds with 100% lithium-6.

Li-7-purified compounds:

The Li-7-purifying compound can be any lithium containing compound having a lithium-7 percentage of the compound that is at least 99% of the total lithium content. This lithium-7 concentration is much higher than the 92.5% natural abundance of lithium-7. The Li-7 purification compound may have a very low lithium-6 concentration (less than 1%) well below the 7.5% native lithium-6 naturalness.

Li-6 enriched compounds:

A Li-6-enriched compound can be any lithium containing compound having a percentage of lithium-6 present in the compound greater than 10% but less than 95% of the total lithium content. 10% lithium-6 is significantly greater than the natural lithium-6 abundance of 7.5%. The lithium-6 concentration in the Li-6-enriched compound can in principle be varied arbitrarily, but - in practical terms - it may be possible to control the concentration in 10% increments. In certain embodiments, the class of Li-6-enriched compounds is about 10%-25%, about 25%-35%, about 35%-45%, about 45%-55%, about 55%-65%, about lithium-6 concentrations in the approximate range of 65%-75%, about 75%-85% and about 85%-95%. In certain embodiments, the average lithium-6 concentration in the Li-6-enriched compound is about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80% and about 90% can

Li-7 enriched compound:

The Li-7-enriched compound can be any lithium containing compound having a percentage of lithium-7 greater than about 95% but less than about 99% of the total lithium content. The 95% lithium-7 is significantly greater than the natural lithium-7 abundance of 92.5%.

Methods of making and administering isotopically-modified lithium compounds are known in the art and are described, for example, in US Pat. No. 9,044,418, the contents of which are incorporated herein by reference in their entirety.

human equivalent dose of lithium

In certain embodiments, the amount of lithium carbonate in mg/kg daily administered to a human adult is a formula for dose conversion based on body surface area (BSA) (described elsewhere herein), see, e.g., Table II. can be used to extrapolate from the dose of lithium carbonate administered to an experimental animal, eg, a mouse. In certain embodiments, the dosage of lithium carbonate is administered in an amount of mg of lithium carbonate for daily administration to a 60 kg adult human.

Table II: Conversion of mouse lithium carbonate dose (mg/kg) to human equivalent dose (HED) of lithium (mg/kg) based on body surface area

lithium monotherapy

Lithium was first described as a mood stabilizer by Australian psychiatrist John Cade in 1949 for the treatment of acute mania (Cade JF Med J Aust. 1949; 2(10):349-52). Although it has been proposed that lithium's action derives at least in part from the ability of Li+ ions to inhibit inositol monophosphatase and glycogen synthase kinase 3 by replacing magnesium, an essential cofactor for enzyme activity, approved in 1970 by the US Food and Drug Administration. The mechanism of action of lithium remains a mystery (see, eg, US Pat. No. 9,265,764, the contents of which are incorporated herein by reference in their entirety). Lithium is currently widely prescribed for the treatment of bipolar disorder, unipolar depression, treatment-resistant depression, and suicide prevention.

bipolar disorder treatment

Bipolar disorder is a mood disorder characterized by abnormally intense emotional states that occur during discrete periods called "mood episodes." An overly excited or overexcited state is called a manic episode, and an extremely sad or hopeless state is called a depressive episode. Individuals suffering from bipolar disorder experience manic episodes, and also typically depressive episodes or symptoms, or mixed episodes, in which features of both mania and depression appear simultaneously. These episodes are generally separated by periods of “normal” mood, but in some individuals, depression and mania may alternate rapidly, known as rapid cycles. Extreme manic episodes can sometimes lead to psychotic symptoms such as delusions and hallucinations. Patients affected by bipolar disorder have suffered at least one manic or hypomanic (mild manic) episode. Patients with complete mania and depression are referred to as having "bipolar I disorder". Patients with hypomania and depression are described as having "bipolar II disorder". The onset of episodes tends to be acute and symptoms develop over days to weeks.

Symptoms of mania or manic episodes include both mood changes and behavioral changes. Mood changes include: feeling "high" or overly happy or outgoing for a long period of time; and feeling extremely irritable, anxious, "jumpy" or wired. Behavior changes include: talking very quickly, jumping from one thought to another, having racing thoughts; being easily distracted; increased goal-directed activity, such as undertaking a new project; inadequacy of safety; less sleep; having unrealistic beliefs about one's abilities; acting impulsively and engaging in many pleasurable things; and high-risk behaviors such as spending spree, compulsive sex, and compulsive business investments.

Symptoms of depression or depressive episodes include both mood changes and behavioral changes. Mood changes include: prolonged anxious or empty feelings; and loss of interest in activities once enjoyed, including sexual intercourse. Behavioral changes include: feeling tired or "slowed down"; trouble concentrating, remembering, and making decisions; feeling restless or irritable; changing eating, sleeping or other habits; and contemplating death or suicide or attempting suicide.

In adult patients with bipolar disorder, the dose of lithium required to achieve therapeutic efficacy in acute mania typically starts with a dose of about 10 to 15 mg/kg or 600-900 mg of lithium carbonate per day for adults; , which is gradually increased to about 30 mg/kg or 1800 mg per day for an adult human of lithium carbonate. Lithium has traditionally been given in two to four divided doses, but single evening doses have also been used and have been shown to have similar therapeutic efficacy with improved compliance and far fewer renal side effects (Carter et al., 2013; Ljubicic et al., 2013; Ljubicic et al. al., 2008; Singh et al., 2011). The maximum daily dose should not exceed approximately 40 mg/kg or 2400 mg of lithium carbonate in general or for adults. Typical therapeutic concentrations of lithium in serum for the acute treatment of manic episodes range from 0.6 to 1.2 mmol/L, and the number of patients with a positive treatment response increases with increasing serum lithium concentrations.

For long-term control of bipolar disorder (BD) in adults, the recommended dosage is about 15 to 25 mg/kg or 900 to 1500 mg of lithium carbonate/day for an adult human per day. Blood lithium concentrations considered safe for BD maintenance treatment range as low as 0.4 mmol/L to 1.2 mmol/L, with higher end points of the range improving the likelihood of effective prophylactic therapy. However, given concerns about side effects caused by long-term use of lithium, a lower target range of 0.4 to 0.8 mmol/L is often used. In contrast, concentrations between 1.2-2.5 mmol/L can be associated with mild toxicity, concentrations between 2.5 and 3.5 mmol/L result in severe toxicity, and concentrations above 3.5 mmol/L can be life-threatening. .

In pediatric BD patients, dosages of lithium are typically within the range estimates for adults given body size, i.e. 20-30 mg/kg of lithium carbonate per day for acute treatment and lithium carbonate/kg for chronic treatment. 10 to 25 mg.

Dosage in elderly patients should be carefully monitored to account for age-related low renal function, which typically leads to a 2- to 3-fold reduction in the dose required to achieve the desired serum concentration (Rej et al., 2014 ).

Lithium treatment and monitoring during pregnancy is particularly difficult because increased glomerular filtration rate leads to a substantial decrease in lithium levels and a risk of BD recurrence. Therefore, a clinical strategy during pregnancy is to increase the dose of lithium during pregnancy and additionally achieve higher serum levels in the early postpartum period associated with a strong increased risk of recurrence (Deligiannidis et al., 2014). However, as renal function returns to normal in the postpartum period, high lithium doses can cause acute toxicity to the mother as well as to the infant (Horton et al., 2012; Wesseloo et al., 2017).

In adults and children 12 years of age or older suffering from acute mania, the oral dosage of the extended-release lithium tablet may be 900 mg twice daily or 600 mg lithium 3 times daily. For the long-term treatment of mania, in adults and children over 12 years of age, oral doses of lithium may be 600 mg twice daily or up to 1200 mg three times daily. Treatment of mania in children under the age of 12 is not recommended.

Treatment of unipolar depression and prevention of suicide

Unipolar depression or major depressive disorder (MDD) is used as an art-understood term and refers to a diagnosis guided by the diagnostic criteria listed in the DSM-IV or ICD-10 or similar nomenclature (see DSM IV- TR-Desk reference to the diagnostic criteria from DSM-IV-TR, American Psychiatric Association, Washington D.C. 2000; [Kaplan, H. I. et al. Kaplan and Sadock's Synopsis of Psychiatry (8th edition) 1998 Williams & Wilkins, Baltimore]). Unipolar depression is a major clinical problem in Western cultures with an estimated lifetime prevalence of 4%-12%. Although approximately 70% of patients respond to antidepressant treatment, up to 75% suffer a relapse within 10 years, and a very high proportion of patients remain undiagnosed and untreated. Unipolar encompasses the difference between major depression and bipolar depression, and refers to a state that oscillates between depression and mania. Instead, unipolar depression focuses only on a “trough,” characterized by rumination on negative emotions. DSM IV requires the presence of a major depressive episode for a diagnosis of major depression. This in turn consists of at least 5 of 9 symptoms that occur during the same 2-week period, of which depressed mood or loss of interest or pleasure must be one of the symptoms. Other symptoms include changes in weight/appetite, sleep, energy, psychomotor retardation or agitation, guilt, decreased concentration, and suicidal tendencies. Also, it should be noted that depression is not the only mental disorder that leads to suicide. Other disorders such as bipolar disorder, mental disorders (such as schizophrenia), anxiety disorders (including panic disorder, OCD, and PTSD), alcohol and drug addiction, and personality disorders can also lead to suicide.

Lithium is also used as an adjuvant treatment to reduce suicidal tendencies in a patient population with unipolar depression, particularly treatment-resistant depression (Cipriani et al., 2013; Cipriani et al., 2005; Roberts et al., 2017). Lithium was also recommended for the prevention of recurrent unipolar depressive episodes in this population, with the suggestion of initiating prophylactic lifetime treatment after two episodes of severe depression with risk of suicide within 5 years (Abou-Saleh et al. al., 2017; Baldessarini et al., 2003; Post, 2018; Tiihonen et al., 2016; Toffol et al., 2015). Surprisingly, lithium appears to have an anti-suicide effect even at very low concentrations, typically less than 150 μg/L in drinking water (Ando et al., 2017; Vita et al., 2015).

Despite its well-established efficacy in BD treatment, lithium treatment has several drawbacks. The therapeutically effective window is very narrow, and even small changes in serum concentrations can result in, for example, extreme thirst, nausea, vomiting, diarrhea, somnolence, muscle weakness, tremors, lack of coordination, hallucinations, seizures (syncope). or convulsions), vision problems, dizziness, fainting, slow heart rate or rapid or uneven heartbeat. In addition, long-term treatment maintenance among BD patients can be quite variable, with only about 30% of patients showing good long-term efficacy (Scott et al., 2017). Thus, development of a form of lithium with superior therapeutic efficacy in a broader population of BD would dramatically improve BD treatment options.

Based on clinical practice guidelines, lithium has been the first-line treatment for mood stabilization and reduction of suicidal tendencies in bipolar disorder (BD) since 1960, providing acute antimanic treatment palliation and BD relapse for countless BD patients. (Baldessarini et al., 2006; Cipriani et al., 2013; Kessing et al., 2018; Roberts et al., 2017; Sani et al., 2017; Severus et al., 2014). However, despite the widespread use of lithium, it is not uncommon for patients to experience serious side effects from this drug.

For example, the first concern with lithium treatment is undoubtedly the very narrow treatment window, which is 0.6-1.0 mmol/L serum concentrations typically for maintenance of bipolar disorder by caregivers and 1.0 for acute manic treatment. It requires maintaining higher levels of -1.2 mmol/L (Association, 2002; Gelenberg et al., 1989; Grandjean and Aubry, 2009). Continuous monitoring is essential for any treatment with lithium, as lower levels are considered ineffective and lithium serum levels above this range can result in serious side effects and toxicity. This is particularly true in pregnant BD patients, as increases associated with glomerular filtration rate can substantially reduce serum lithium levels to the point where there is a significant risk of BD recurrence.

Acute lithium toxicity may manifest as non-convulsive status epilepticus, slowing of EEG alpha rhythm, pathological 3-10 Hz delta rhythm and diffuse spike discharges, life-threatening coma, hypothonia, and hyporeflexia. (Ivkovic and Stern, 2014; Madhusudhan, 2014; Megarbane et al., 2014; Schou et al., 1968).

Additionally, chronic side effects associated with long-term maintenance lithium therapy include hypothyroidism, renal diabetes insipidus, and renal toxicity and chronic kidney disease, particularly in patients already diagnosed with renal failure (Davis et al., 2018a; Davis et al., 2018b). In an epidemiological study examining reasons for discontinuation of lithium therapy among patients with BD, the majority (62%) discontinued lithium because of side effects, primarily renal disease, diarrhea and/or tremors (Ohlund et al., 2018). In 2014 alone, 6,850 cases of lithium toxicity were reported in the United States. Lithium treatment therefore requires very careful monitoring and titration of serum lithium concentrations to achieve long-lasting therapeutic benefit.

Accordingly, there is an ongoing need for improved treatment options that alleviate the side effects associated with lithium treatment of many severe psychiatric disorders, including bipolar disorder.

ketamine

Ketamine is a drug with dissociative and glutamate NMDA receptor-blocking properties approved by the US Food and Drug Administration in 1970 for anesthetic use. This has been the target of studies of antidepressant effects occurring within hours at subanesthetic doses. Reports of a reduction in suicidal ideation after ketamine infusion are promising, but confirmation of the results for major depression is based on measures of suicidal ideation using a single item on the depression list, no control group, use of a saline control group, mixed diagnosis or suicidal ideation. Limited by the use of low-quality samples.

Clinical trials have established the efficacy of ketamine for reducing suicidal ideation. An example can be found at ClinicalTrials.gov identifier: NCT01700829 as described in a related publication (Grunebaum et al., 2018). This trial demonstrates the adjuvant intravenous use of ketamine compared to the short-acting benzodiazepine narcotic midazolam in patients with major depressive disorder with clinically significant suicidal ideation, as assessed by scores on the Suicidal Ideation Scale (SSI). It is a randomized clinical trial of infusion. The primary outcome measure was the SSI score 24 hours after infusion. Other outcome measures include overall depression rating, clinical rating and safety measures during the 6-week open-label follow-up treatment. IV ketamine was effective in treating acute cases of suicidal tendencies (Lee et al. (2015) Innov Clin Neurosci. 2015 Jan-Feb; 12(1-2): 29-31). Janssen Pharmaceuticals has obtained FDA approval for the purified S-enantiomer of ketamine, also known as esketamine, and marketed it under the brand name Spravato® Esketamine. Spravato® is approved for the treatment of treatment-resistant depression and depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior (see Spravato® prescribing information). More information about esketamine can be found at ClinicalTrials.gov identifier: NCT01627782 and the Spravato ^™ esketamine product label.

Human Equivalent Dose (HED)

Doses of agents administered to laboratory animals, e.g. rodents, can be extrapolated to human equivalent doses (HED) using, e.g., body surface area (BSA) methods (see e.g., the "Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers" (July 2005)], which is available on FDA's website, www.fda.gov/files/drugs/published/Estimating-the-Maximum -Safe-Starting-Dose-in-Initial-Clinical-Trials-for-Therapeutics-in-Adult-Healthy-Volunteers.pdf, the contents of which are incorporated herein by reference in their entirety; see Table III below) .

The Human Equivalent Dose (HED) can be calculated using the equation:

HED (mg/k) = animal dose (mg/kg) x (animal K _m /human K _m ).

Here, K _m refers to a conversion factor in kg/m ² equal to body weight in kg divided by surface area in m ² . Thus, human equivalent doses (mg/kg) or daily doses (mg) were administered to adult humans. Humans can be extrapolated from the daily dose (mg/kg) of drug administered to mice.

Table III

Conversion of animal doses to human equivalent doses based on body surface area

SAGE-217 is an investigational medication under development by SAGE Therapeutics for the treatment of major depressive disorder, postpartum depression, essential tremor, Parkinson's disease, insomnia and seizures. It is a synthetic, orally active, inhibitory pregnane neurosteroid and acts as a positive allosteric modulator of the GABA _A receptor. The drug was developed as an improvement of allopregnanolone (brexanolone) with high oral bioavailability and a biological half-life suitable for once-daily administration. As of February 2018, SAGE-217 is undergoing phase 2 clinical trials for major depressive disorder, postpartum depression, essential tremor, and Parkinson's disease, and phase 1 clinical trials for insomnia and seizures. It is also in a preclinical stage of development for dyskinesia. The formula for SAGE-217 is 3α-hydroxy-3β-methyl-21-(4-cyano-1H-pyrazol-1′-yl)-19-nor-5β-pregnan-20-one; 3β-methyl-21-(4-cyano-1H-pyrazol-1′-yl)-19-norpregnanolone; 3α-hydroxy-3β-methyl-5β-dihydro-21-(4-cyano-1H-pyrazol-1′-yl)-19-norprogesterone.

Combination of deuterated gaboxadol and lithium

A largely automated drug-screening platform, referred to as “Pharmacomapping,” involves whole-brain detection of drug-induced neuronal activation expressed in drug-induced expression of an early-stage gene (IEG), such as c-fos . PharmacoMapping is commercially available as a paid service from CRO Certerra, Inc., Farmingdale, New York.

Pharmacomapping of mouse or rat brain activity in response to various antipsychotic drugs, including antipsychotics, antidepressants, stimulants and anxiolytics (Engber et al., 1998; Kiss, 2018; Salminen et al., 1996; Semba et al. ., 1996; Slattery et al., 2005; Sumner et al., 2004) confirmed that c-fos activation imaging in the rodent brain is an effective method for screening antipsychotic drugs (Sumner et al., 2004).

The therapeutic efficacy of deuterated gaboxadol in the treatment method according to the present invention is shown by the results using the pharmacomapping approach as presented in the Examples. Among other things, the examples herein show, using pharmacomapping, that deuterated gaboxadol affects activation in the mouse brain and that this effect corresponds to the effect of lithium and that of ketamine in the brain. An enhanced effect is observed when the drug is used in combination with lithium, particularly deuterated gaboxadol. It is further observed that the combination therapy has effects that can be described as additive or synergistic. Based on these data, doses comparable to standard human doses of lithium are believed to be suitable for use in combination with deuterated gaboxadol. Further, based on these data, doses below standard human doses of lithium, sometimes referred to herein as “substandard doses of lithium,” are believed to be suitable for use in combination with deuterated gaboxadol.

Using the empirical approach of pharmacomapping, deuterated gaboxadol, in Example 19 and Figures 34-38 , in combination with standard and substandard doses of lithium, in Example 15 and Figures 29 It has been shown to activate c-fos expression in the same regions of the brain as seen with standard therapeutically effective lithium monotherapy. Importantly, the brains of mice receiving low doses of deuterated gaboxadol alone or subnormal doses of lithium alone did not induce any detectable or significant c-fos activity. As a result, low doses of deuterated gaboxadol (e.g., daily or less frequently in the range of 1-20 mg) and substandard doses of lithium, or one or both of its compounds, are considered pharmaceutically acceptable. Combination therapies using acceptable salts have been shown to be effective, wherein substandard doses are lower than those normally used in monotherapy, and adverse effects associated with the higher doses of lithium used in monotherapy are generally reduced or prevented. expected to be

Additionally, standard doses of lithium also act in combination (i.e., synergistically and/or additively) with deuterated gaboxadol (Example 19 ), indicating that gaboxadol is particularly effective in conventional monotherapy. This suggests that existing lithium monotherapy can be augmented in patients who do not respond or relapse.

Substandard doses of lithium

In certain embodiments, a “substandard” dose of lithium is defined as a human equivalent dose of lithium carbonate that induces only low or no detectable induction of brain c-fos signaling when applied to an animal such as a mouse. do.

In certain embodiments, a “substandard” dose of lithium is a daily dose of lithium carbonate that cannot treat depression, treatment-resistant depression, acute suicidal tendencies, or bipolar disorder by itself, ie, as lithium monotherapy. In certain embodiments, a “substandard” dose of lithium in humans is a daily dose of less than about 10 mg lithium carbonate/kg, which corresponds to a dose of less than about 600 mg lithium carbonate/day for an adult human. am. For comparison purposes, the corresponding “substandard” dose of lithium in mice is a daily dose of less than about 120 mg/kg of lithium carbonate.

In certain embodiments, a "substandard" daily dose of lithium for an adult human patient is about 50-600 mg lithium carbonate, about 55-600 mg lithium carbonate, about 60-600 mg lithium carbonate, about 65-600 mg Lithium carbonate, about 70-600 mg lithium carbonate, about 75-600 mg lithium carbonate, about 80-600 mg lithium carbonate, about 85-600 mg lithium carbonate, about 90-600 mg lithium carbonate or about 95-600 mg lithium carbonate , about 100-600 mg lithium carbonate, about 105-600 mg lithium carbonate, about 110-600 mg lithium carbonate, about 115-100 mg lithium carbonate, about 120-100 mg lithium carbonate, about 125-600 mg lithium carbonate, about 130-600 mg lithium carbonate, about 135-600 mg lithium carbonate, about 140-600 mg lithium carbonate, about 145-600 mg lithium carbonate, about 150-600 mg lithium carbonate, about 155-600 mg lithium carbonate, about 160- 600 mg lithium carbonate, about 165-600 mg lithium carbonate, about 170-600 mg lithium carbonate, about 175-600 mg lithium carbonate, about 180-600 mg lithium carbonate, about 185-600 mg lithium carbonate, about 190-600 mg Lithium carbonate, about 195-600 mg Lithium carbonate, about 200-600 mg Lithium carbonate, About 215-600 mg Lithium carbonate, About 210-600 mg Lithium carbonate, About 215-100 mg Lithium carbonate, About 220-100 mg Lithium carbonate , about 225-600 mg lithium carbonate, about 230-600 mg lithium carbonate, about 235-600 mg lithium carbonate, about 240-600 mg lithium carbonate, about 245-600 mg lithium carbonate, about 250-600 mg lithium carbonate, about 255-600 mg lithium carbonate, about 260-600 mg lithium carbonate, about 265-600 mg lithium carbonate, about 270-600 mg lithium carbonate, about 275-600 mg lithium carbonate, about 280-600 mg lithium carbonate, about 285-600 mg lithium carbonate 600 mg lithium carbonate, about 290-600 mg lithium carbonate, about 295-600 mg lithium carbonate, about 300-600 mg charcoal Lithium acid, about 315-600 mg Lithium carbonate, about 310-600 mg Lithium carbonate, About 315-600 mg Lithium carbonate, About 320-600 mg Lithium carbonate, About 325-600 mg Lithium carbonate, About 330-600 mg Lithium carbonate , about 335-600 mg lithium carbonate, about 340-600 mg lithium carbonate, about 345-600 mg lithium carbonate, about 350-600 mg lithium carbonate, about 355-600 mg lithium carbonate, about 360-600 mg lithium carbonate, about 365-600 mg lithium carbonate, about 370-600 mg lithium carbonate, about 375-600 mg lithium carbonate, about 380-600 mg lithium carbonate, about 385-600 mg lithium carbonate, about 390-600 mg lithium carbonate or about 395-600 mg lithium carbonate It refers to a daily dosage in the range of 600 mg lithium carbonate.

In certain embodiments, a "substandard" daily dose of lithium for a human adult patient is about 50-600 mg lithium carbonate, 50-595 mg lithium carbonate, 50-590 mg lithium carbonate, 50-585 mg lithium carbonate, 50-580 mg lithium carbonate, 50-575 mg lithium carbonate, 50-570 mg lithium carbonate, 50-565 mg lithium carbonate, 50-560 mg lithium carbonate, 50-555 mg lithium carbonate, 50-550 mg lithium carbonate, 50 -545 mg lithium carbonate, 50-540 mg lithium carbonate, 50-535 mg lithium carbonate, 50-530 mg lithium carbonate, 50-525 mg lithium carbonate, 50-520 mg lithium carbonate, 50-515 mg lithium carbonate, 50- 510 mg lithium carbonate, 50-505 mg lithium carbonate, 50-500 mg lithium carbonate, 50-495 mg lithium carbonate, 50-490 mg lithium carbonate, 50-485 mg lithium carbonate, 50-480 mg lithium carbonate, 50-475 mg lithium carbonate, 50-470 mg lithium carbonate, 50-465 mg lithium carbonate, 50-460 mg lithium carbonate, 50-455 mg lithium carbonate, 50-450 mg lithium carbonate, 50-445 mg lithium carbonate, 50-440 mg Lithium carbonate, 50-435 mg Lithium carbonate, 50-430 mg Lithium carbonate, 50-425 mg Lithium carbonate, 50-420 mg Lithium carbonate, 50-415 mg Lithium carbonate, 50-410 mg Lithium carbonate, 50-405 mg Carbonate Lithium, 50-400 mg lithium carbonate, about 50-395 mg lithium carbonate, about 50-390 mg lithium carbonate, about 50-385 mg lithium carbonate, about 50-380 mg lithium carbonate, about 50-375 mg lithium carbonate, about 50-370 mg lithium carbonate, about 50-365 mg lithium carbonate, about 50-360 mg lithium carbonate, about 50-355 mg lithium carbonate, about 50-350 mg lithium carbonate, about 50-345 mg lithium carbonate, about 50- 340 mg lithium carbonate, about 50-335 mg lithium carbonate, about 50-330 mg lithium carbonate, about 50-325 mg lithium carbonate, about 50-320 mg lithium carbonate, about 50-315 m g lithium carbonate, about 50-3500 mg lithium carbonate, about 50-305 mg lithium carbonate, about 50-300 mg lithium carbonate, about 50-300 mg lithium carbonate, about 50-295 mg lithium carbonate, about 50-290 mg carbonate Lithium, about 50-285 mg lithium carbonate, about 50-280 mg lithium carbonate, about 50-275 mg lithium carbonate, about 50-270 mg lithium carbonate, about 50-265 mg lithium carbonate, about 50-260 mg lithium carbonate, About 50-255 mg lithium carbonate, about 50-250 mg lithium carbonate, about 50-245 mg lithium carbonate, about 50-240 mg lithium carbonate, about 50-235 mg lithium carbonate, about 50-230 mg lithium carbonate, about 50 -225 mg lithium carbonate, about 50-220 mg lithium carbonate, about 50-215 mg lithium carbonate, about 50-210 mg lithium carbonate, about 50-205 mg lithium carbonate, about 50-200 mg lithium carbonate, about 50-195 mg lithium carbonate, about 50-190 mg lithium carbonate, about 50-185 mg lithium carbonate, about 50-180 mg lithium carbonate, about 50-175 mg lithium carbonate, about 50-170 mg lithium carbonate, about 50-165 mg carbonate Lithium, about 50-160 mg lithium carbonate, about 50-155 mg lithium carbonate, about 50-150 mg lithium carbonate, about 50-145 mg lithium carbonate, about 50-140 mg lithium carbonate, about 50-135 mg lithium carbonate, About 50-130 mg lithium carbonate, about 50-125 mg lithium carbonate, about 50-120 mg lithium carbonate, about 50-115 mg lithium carbonate, about 50-110 mg lithium carbonate, about 50-105 mg lithium carbonate, about 50 -100 mg lithium carbonate, about 50-95 mg lithium carbonate, about 50-90 mg lithium carbonate, about 50-85 mg lithium carbonate, about 50-80 mg lithium carbonate, about 50-75 mg lithium carbonate, about 50-70 mg lithium carbonate, about 50-65 mg lithium carbonate, about 50-60 mg lithium carbonate, or about 50-55 mg lithium carbonate per day.

standard dose of lithium

In certain embodiments, a “standard” dose of lithium is a daily dose of lithium that induces brain c-fos signaling in an animal model, such as a mouse, by itself, i.e., as a single dose.

In certain embodiments, a “standard” dose of lithium is, by itself, a daily dose of lithium at which lithium monotherapy can treat depression, treatment-resistant depression, acute suicidal tendencies, or bipolar disorder.

In certain embodiments, a “standard” dose of lithium is a daily dose of greater than about 10 mg/kg of lithium carbonate, corresponding to a dose of greater than about 600 mg lithium carbonate/day for an adult human.

In certain embodiments, a “standard” dose of lithium in mice is a daily dose ranging from about 120 mg/kg to about 480 mg/kg of lithium carbonate. Human equivalent doses correspond to doses in the range of about 600 mg to about 2400 mg lithium carbonate/day for a 60 kg adult human, about 10 mg/kg and 40 mg/kg, respectively.

In certain embodiments, a “standard” daily dosage of lithium for an adult human patient refers to a daily dosage in the range of about 600-2400 mg lithium carbonate.

In certain embodiments, a “standard” daily dosage of lithium for an adult human patient refers to a daily dosage in the range of about 600-2400 mg lithium carbonate.

In certain embodiments, a “standard” daily dosage of lithium for an adult human patient is about 600-2350 mg lithium carbonate, about 600-2300 mg lithium carbonate, about 600-2250 mg lithium carbonate, about 600-2200 mg Lithium carbonate, about 600-2150 mg Lithium carbonate, about 600-2100 mg Lithium carbonate, About 600-2050 mg Lithium carbonate, About 600-2000 mg Lithium carbonate, About 600-1950 mg Lithium carbonate, About 600-1900 mg Lithium carbonate , about 600-1850 mg lithium carbonate, about 600-1800 mg lithium carbonate, about 600-1750 mg lithium carbonate, about 600-1700 mg lithium carbonate, about 600-1650 mg lithium carbonate, about 600-1600 mg lithium carbonate, about 600-1550 mg lithium carbonate, about 600-1500 mg lithium carbonate, about 600-1450 mg lithium carbonate, about 600-1400 mg lithium carbonate, about 600-1350 mg lithium carbonate, about 600-1300 mg lithium carbonate, about 600- 1250 mg lithium carbonate, about 600-1200 mg lithium carbonate, about 600-1150 mg lithium carbonate, about 600-1100 mg lithium carbonate, about 600-1050 mg lithium carbonate, about 600-1000 mg lithium carbonate, about 600-950 mg Lithium carbonate, about 600-900 mg lithium carbonate, about 600-850 mg lithium carbonate, about 600-800 mg lithium carbonate, about 600-750 mg lithium carbonate, about 600-700 mg lithium carbonate, or about 600-650 mg carbonate Refers to a range of daily doses of lithium.

In certain embodiments, a “standard” daily dosage of lithium for an adult human patient is about 600-2400 mg lithium carbonate, about 650-2400 mg lithium carbonate, about 700-2400 mg lithium carbonate, About 750-2400 mg lithium carbonate, about 800-2400 mg lithium carbonate, about 850-2400 mg lithium carbonate, about 900-2400 mg lithium carbonate, about 950-2400 mg lithium carbonate, about 1000-2400 mg lithium carbonate, about 1050 -2400 mg lithium carbonate, about 1050-2400 mg lithium carbonate, about 1100-2400 mg lithium carbonate, about 1150-2400 mg lithium carbonate, about 1200-2400 mg lithium carbonate, about 1250-2400 mg lithium carbonate, about 1300-2400 mg lithium carbonate, about 1350-2400 mg lithium carbonate, about 1400-2400 mg lithium carbonate, about 1450-2400 mg lithium carbonate, about 1500-2400 mg lithium carbonate, about 1550-2400 mg lithium carbonate, about 1600-2400 mg carbonic acid Lithium, about 1650-2400 mg lithium carbonate, about 1700-2400 mg lithium carbonate, about 1750-2400 mg lithium carbonate, about 1800-2400 mg lithium carbonate, about 1850-2400 mg lithium carbonate, about 1900-2400 mg lithium carbonate, About 1950-2400 mg lithium carbonate, about 2000-2400 mg lithium carbonate, about 2050-2400 mg lithium carbonate, about 2100-2400 mg lithium carbonate, about 2150-2400 mg lithium carbonate, about 2200-2400 mg lithium carbonate, about 2250 -2400 mg lithium carbonate, refers to a daily dosage in the range of about 2300-2400 mg lithium carbonate or about 2350-2400 mg.

Synergistic combination of deuterated gaboxadol and lithium

The present invention also discloses the discovery that deuterated gaboxadol and lithium are expected to provide improved therapeutic treatment of psychiatric disorders as they act synergistically. An explanation of what is considered "synergism" follows.

In certain embodiments, the effective amounts of lithium and deuterated gaboxadol are synergistic amounts. As used herein, "synergistic" is used within its art-accepted meaning. Thus, the synergistic combination of lithium and deuterated gaboxadol exhibits more than the additive effect of each (lithium and deuterated gaboxadol) alone.

In certain embodiments, administering a synergistic combination of lithium and deuterated gaboxadol to a subject in need thereof can: 1) motor (MO), gustatory (GU), instinctive (VISC), agranular lateral fossa Cortex (AI), Voice (SS), Auditory, Visual (VIS), Auditory (AUD), Prelimbic (PL) and Inferior Limb (ILA), Occipital Lobe (RSP), Parietal Parietal (PTL), Temporal Union (TEa) , wide cortical activation, including external olfactory (ECT), internal olfactory (ENT), periolfactory (PERI), cutaneous (PIR), and anterior cingulate (ACA) cortices, anterior cingulate (CLA); as well as 2) hippocampal CA1 area, stratified nuclear demarcation striatum (BST), central amygdala (CEA), cortical amygdala (COA), basolateral and basolateral amygdala (BLA and BMA), medial amygdala (MEA), thalamic ventromedial posteromedial nucleus (VPM), subparascapular nucleus (SPF), medial geniculate complex (MG), anterior geniculate nucleus (SGN), nucleus of recombination (RE), rhomboid nucleus (RH), and medial central nucleus of the thalamus (CM) ), paraventricular nucleus, hypothalamic nucleus (PVH), posteromedial nucleus of the hypothalamus (DMH), mammary nucleus (TM), parathalamic nucleus (PSTN) and hypothalamic nucleus (STN), brachial nucleus, lumbar nucleus (LC) Activates c-fos signaling in at least one region, at least two regions or at least three regions of the brain of an animal model selected from the group consisting of , and subcortical activation involving the nucleus to isolate (NTS) .

In certain embodiments, administering a synergistic combination of lithium and deuterated gaboxadol to a subject in need thereof can reduce at least 1, 2, 3 brains of an animal model also activated by lithium monotherapy. or activates c-fos signaling in more regions.

In certain embodiments, administering a synergistic combination of lithium and deuterated gaboxadol to a subject in need thereof results in at least one, two brains of an animal model also activated by deuterated gaboxadol monotherapy. Activate c-fos signaling in three, three or more regions.

In certain embodiments, the synergistic combination of lithium and deuterated gaboxadol comprises subnormal doses of lithium as described herein. In certain embodiments, the synergistic combination of lithium and deuterated gaboxadol comprises a standard dosage of lithium as described herein.

In certain embodiments, the synergistic combination of lithium and deuterated gaboxadol comprises dosages of deuterated gaboxadol as described herein.

In certain embodiments, a subnormal dose of lithium is administered with a dose of deuterated gaboxadol as exemplified in Example 19 .

In certain embodiments, the synergistic combination of lithium and deuterated gaboxadol is administered daily to an adult human patient in the range of about 50-600 mg lithium carbonate and about 1 to about 30 mg deuterated gaboxadol. include the quantity

In certain embodiments, the synergistic combination of lithium and deuterated gaboxadol is administered daily to an adult human patient in the range of about 50-600 mg lithium carbonate and about 5 to about 10 mg deuterated gaboxadol. include the quantity

In certain embodiments, a synergistic combination of lithium and deuterated gaboxadol is administered in an amount ranging from about 600 mg to about 2400 mg lithium carbonate and from about 1 to about 30 mg deuterated gaboxadol for an adult human patient. Includes a daily dose.

In certain embodiments, a synergistic combination of lithium and deuterated gaboxadol is administered in an amount ranging from about 600 mg to about 2400 mg lithium carbonate and from about 5 to about 10 mg deuterated gaboxadol for an adult human patient. Includes a daily dose.

Several types of synergism are recognized by those skilled in the art. By way of example, some synergism can be recognized in a 1 + 1 = 3 fashion, where the resulting effect of the combination exceeds the additive of the compounds administered individually. As another example, another synergism is 0 + 0 = 1 of a kind, where the resulting effect of the combination exceeds the additive of the compounds administered individually, which proves ineffective individually (at given test doses). Both compounds demonstrate sufficient efficacy when administered together. The latter synergism is considered particularly pronounced when the test compounds are not known to act through similar or related pathways.

In certain embodiments, the synergistic combination of lithium and deuterated gaboxadol does not include lithium and deuterated gaboxadol in a 1:1 molar ratio.

In certain embodiments, the synergy between lithium and deuterated gaboxadol is at least about 5%, 10%, 20% greater than the sum of the effects of lithium alone and deuterated gaboxadol alone on brain c-fos signaling. , 30%, 40%, 50%, 100%, 200%, 400%, 500% or 1000% of the brains of larger animal models, the outpost genes (e.g., c-fos , arc , egr-1 , fosb and npas4 ).

In certain embodiments, the synergy between lithium and deuterated gaboxadol is at least about 5%, 10%, 20% greater than the sum of the effects of lithium alone and deuterated gaboxadol alone on brain c-fos signaling. , resulting in activation of c-fos gene expression in the brain of animal models that are 30%, 40%, 50%, 100%, 200%, 400%, 500% or 1000% larger.

In certain embodiments, an outpost gene (e.g., c-fos , arc , egr-1) in the brain of an animal model equal to the sum of the effects of lithium alone and deuterated gaboxadol alone on brain c-fos signaling. , there is an additive effect between lithium and deuterated gaboxadol resulting in activation of fosb and npas4 ).

In certain embodiments, lithium and deuterated gaboxadol resulting in activation of the early c-fos gene in the brain of an animal model equal to the sum of the effects of lithium alone and deuterated gaboxadol alone on brain c- fos signaling. There is an additional effect between stones.

In certain embodiments, the "additional combination" of lithium and deuterated gaboxadol comprises a subnormal dose of lithium as described herein.

In certain embodiments, the “additional combination” of lithium and deuterated gaboxadol comprises a standard dosage of lithium as described herein.

In certain embodiments, the “additional combination” of lithium and deuterated gaboxadol comprises a low dose of deuterated gaboxadol as described herein.

In certain embodiments, the "additional combination" of lithium and deuterated gaboxadol comprises a standard dosage of deuterated gaboxadol as described herein.

In certain embodiments, the “additional combination” of lithium and deuterated gaboxadol does not include lithium and deuterated gaboxadol in a 1:1 molar ratio.

In certain embodiments, lithium and deuterated gaboxadol can be administered as separate compositions (they are formulated separately) or together (they are formulated together) for combination therapy. In certain embodiments, lithium and deuterated gaboxadol may be administered simultaneously, simultaneously, sequentially or synchronously as provided herein.

Treatment of Mental Disorders with a Combination of Deuterated Gaboxadol and Lithium

Based on similarities between pharmacomab and conventional lithium monotherapy between deuterated gaboxadol and lithium combination therapy (see Examples 15 and 19 herein), deuterated gaboxadol can be used to treat, but not limit, bipolar disorder , enhances the established activity of lithium in the treatment of psychiatric disorders such as depression, treatment-resistant depression and acute suicidal tendencies (see above).

Thus, in certain embodiments, a method comprising administering a combination of deuterated gaboxadol and lithium, or a pharmaceutically acceptable salt of either or both of these compounds, to a patient in need thereof for treatment of a psychiatric disorder. A method of treating a mental disorder that causes

In certain embodiments, the efficacy of treatment can be monitored by a physician using a disease-specific mental state assessment scale. Mental status rating scales refer to psychological tests that have been developed to provide a reliable and objective method for monitoring the severity of symptoms of certain mood disorders and for measuring response to treatment, see, for example, in the Handbook of Clinical Ratings [Handbook of Clinical Ratings]. scales and assessment in psychiatry and mental health by Baer, Lee and Blais, Mark A. New York; Humana Press, 2010; ISBN: 9781588299666, the contents of which are incorporated herein by reference in their entirety. Exemplary mental state rating scales include, but are not limited to:

Beck Depression Inventory (BDI), Beck Hopelessness Scale, Center for Epidemiological Studies-Depression Scale (CES-D), Center for Epidemiological Studies-Depression Scale (CES-D), Center for Epidemiological Studies-Depression for Children Scale (CES-DC), Edinburgh Postnatal Depression Scale (EPDS), Geriatric Depression Scale (GDS), Hamilton Depression Rating Scale (HAM-D), Hospital Anxiety and Depression Scale, Kutcher ) Adolescent Depression Scale (KADS), Major Depression Inventory (MDI), Montgomery-Asberg Depression Rating Scale (MADRS), PHQ-9, Mood and Emotion Questionnaire (MFQ), Weinberg Screen Affective Scale , WSAS) and Zung Self-Rating Depression for Depression, Altman Self-Rating Mania Scale (ASRM), Bipolar Spectrum Diagnostic Scale, Child Mania Rating Scale, General Behavior List, Hypomania Checklist, Mood Disorder Questionnaire (MDQ), Young Mania Rating Scale (YMRS) for Mania and Bipolar Disorder, and SAD PERSONS Scale for Suicide Risk.

In certain regimens, efficacy of treatment can be assessed by physicians using EEG recordings during and after drug combination application, along with drug-induced biomarker changes in the EEG based on drug-induced biomarker changes established preclinically in animal models. can be monitored by

Preferably, deuterated gaboxadol and lithium are administered to the patient approximately simultaneously. Gaboxadol is eliminated from the body at a known rate. Administration of lithium at one time after gaboxadol has been cleared from the patient's body is not expected to be as effective as administration of both deuterated gaboxadol and lithium at approximately the same time. Most preferably, deuterated gaboxadol and lithium are administered simultaneously. In cases where lithium is administered to the patient more than once daily, deuterated gaboxadol is also preferably administered on the same dosing(s) schedule.

Formulations of deuterated gaboxadol and lithium

The combination of deuterated gaboxadol and lithium may be administered synchronously or separated in time in separate dosage forms, or may by definition be administered in a single combination fixed dosage form administered concurrently. For independent administration, any of the previously described dosage forms may be used. The following section details the fixed-dose combination of deuterated gaboxadol and lithium.

Methods of administering a fixed dose combination of deuterated gaboxadol and lithium, or a pharmaceutically acceptable salt of one or both of these compounds, include, but are not limited to, oral, subcutaneous, intradermal, intramuscular (by way of non-limiting example, intramuscular depots, such as those described in U.S. Patent No. 6,569,449, the contents of which are incorporated herein in their entirety), intraperitoneal, intravenous, intranasal, epidural, sublingual, intranasal, intracerebral, This includes intravaginal, transdermal, rectal, inhalation or topical, especially to the ears, nose, eyes or skin. The mode of administration may be left to the discretion of the physician. In most instances, administration should result in the release of a compound described herein or a pharmaceutically acceptable salt thereof into the bloodstream.

In certain embodiments, the present invention contemplates administration of a fixed dose combination of deuterated gaboxadol and lithium designed for rapid onset of therapeutic effect, or a pharmaceutically acceptable salt of one or both of these compounds. . A wide variety of dosage forms may be used, including those previously described in the literature. A preferred dosage form is suitable for oral or intranasal administration. Compositions for oral delivery may be in the form of tablets, lozenges, aqueous or oily suspensions, solutions, granules, capsules, powders, pills, pellets, liquid-containing capsules, emulsions, syrups or elixir suppositories, sustained release formulations, or any suitable for use. may be of different shapes.

Orally administered fixed dose combination compositions may contain one or more agents, for example sweeteners such as fructose, aspartame or saccharin; flavoring agents such as oil of peppermint, cherry or wintergreen; coloring agent; and preservatives. Moreover, when in tablet or pill form, the composition may be coated to delay disintegration and absorption in the gastrointestinal tract, thus providing a sustained action over an extended period of time. Selectively permeable membranes surrounding the osmotically active compounds of the present invention are also suitable for oral administration. In this latter platform, fluid from the environment surrounding the capsule is absorbed by the covalent compound, which expands and displaces the agent or agent composition through the orifice. Such delivery platforms can provide an essentially zero order delivery profile unlike the spiked profile of immediate release formulations. Time delay materials such as glycerol monostearate or glycerol stearate may also be useful. Oral compositions may include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose and magnesium carbonate. In one embodiment, the excipient is of pharmaceutical grade.

The fixed-dose compositions herein may optionally include pharmaceutically acceptable excipients in appropriate amounts to provide a form suitable for administration to a subject. The pharmaceutical excipients may be liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil and sesame oil, and the like. Pharmaceutical excipients may be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica and urea, and the like. Also, adjuvants, stabilizers, thickeners, lubricants and colorants may be used. In one embodiment, the pharmaceutically acceptable excipient is sterile when administered to a subject. Water is a useful excipient when a compound of the present invention or a pharmaceutically acceptable salt thereof is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, particularly for injectable solutions. Suitable pharmaceutical excipients are also starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, glycerol, propylene, glycol, water and ethanol. Include etc. In addition, the compositions herein may include minor amounts of wetting or emulsifying agents, or pH buffering agents, if desired. Other examples of suitable pharmaceutical excipients are described in Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro eds., 19th ed. 1995), which is incorporated herein by reference in its entirety.

A particularly preferred form for rapid onset is an orally disintegrating dosage form (ODDF) that provides immediate release in the oral cavity of the patient enhancing oral absorption of the drug. ODDF and their use in the present invention are described above in relation to the use of deuterated gaboxadol. ODDF can also be used for a fixed dose combination of deuterated gaboxadol and lithium.

In certain embodiments, the fixed dose compositions described herein may be administered by controlled release or sustained release means or other delivery devices well known to those skilled in the art. Examples include, but are not limited to, U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,556, each of which is incorporated herein by reference in its entirety. Such dosage forms may include, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof to provide the desired release profile in varying proportions. It may be useful to provide controlled or sustained release of one or more active ingredients employed. Suitable controlled-release or sustained-release formulations known to those skilled in the art, including those described herein, are used in combination with a synergistic combination of deuterated gaboxadol and lithium, or a pharmaceutically acceptable salt of one or both of these compounds. can be easily selected for Accordingly, in certain embodiments, the present invention provides single unit dosage forms adapted for oral administration such as, but not limited to, tablets, capsules, gel caps and caplets suitable for controlled or sustained release. In certain embodiments, a single unit dose of the ingredients may be administered individually or mixed together, e.g., as a dry lyophilized powder or water-free concentrate in a hermetically sealed container such as an ampoule or sachet indicating the amount of active agent. is supplied When the compounds described herein or pharmaceutically acceptable salts thereof are to be administered by infusion, they can be dispensed with, for example, an infusion bottle containing sterile pharmaceutical grade water or saline. When the compound described herein or a pharmaceutically acceptable salt thereof is administered by injection, an ampoule of sterile water for injection or saline may be provided so that the components may be mixed prior to administration.

dosing regimen

The dosing regimen utilizing a combination of deuterated gaboxadol and lithium, or a pharmaceutically acceptable salt of one or both of these compounds, will depend on the type, species, age, weight, sex and medical condition of the subject; severity of the condition being treated; route of administration; the subject's kidney or liver function; and the particular compound of the present invention used.

The combination of deuterated gaboxadol and lithium, or a pharmaceutically acceptable salt of one or both of these compounds, can be administered in a single daily dose, or the total daily administration is two, three or four times. It may be administered in divided doses.

In certain embodiments, the combination of deuterated gaboxadol and lithium, or a pharmaceutically acceptable salt of one or both of these compounds, is, for example, 400 mg/10 mg, 400 mg/5 mg, 300 mg/ It can be administered as a capsule with a dosage of lithium carbonate/deuterated gaboxadol of 10 mg, 300 mg/5 mg, 200 mg/5 mg or 100 mg/5 mg.

In certain embodiments, the combination of deuterated gaboxadol and lithium is administered as a controlled release medicament. In certain embodiments, controlled-release is the release of a substance (eg, lithium and/or deuterated gaboxadol) at a selected or otherwise controllable rate, interval, and/or amount, which is substantially influenced by the environment of use. do not receive Thus “controlled release” can be, without limitation, substantially continuous delivery or patterned delivery (eg, intermittent delivery over a period of time interrupted by regular or irregular time intervals). In certain embodiments, drug delivery is “patterned,” such that drug delivery is patterned for pre-selected periods of time (e.g., in addition to periods associated with bolus injections), generally following a substantially regular pattern. achieve In certain embodiments, delivery is “patterned,” such that drug delivery increases, decreases, is substantially constant, or is pulsatile, at a rate or range of rates (e.g., amount of drug per unit time, or per unit time). volume of the drug formulation), and may further be continuous, substantially continuous, or chronic delivery.

In certain embodiments, an adult human diagnosed with bipolar disorder can be treated, for example, as follows. For acute treatment, for example in the case of mania or hypomania, a daily dose of about 50 to about 1800 mg of lithium carbonate, targeted to achieve a lithium serum level of about 0.4 to about 1.5 mmol/L, is deuterated. from about 1 to about 30 mg of gaboxadol monohydrate. For chronic prophylactic treatment, for example in case of mania or hypomania, a daily dosage of about 50 to about 900 mg of lithium carbonate targeted to achieve a lithium serum level of about 0.2 to about 1.2 mmol/L is, from about 1 to about 30 mg of deuterated gaboxadol monohydrate.

kit

A kit for treating a mental disorder comprises one or a plurality of deuterated gaboxadol dosage forms, optionally in one or more containers, with or without lithium, ketamine or other pharmaceutical dosage forms, and administered according to a predetermined dosing regimen. Instructions for administering the form are included. In kit embodiments using a combination of deuterated gaboxadol and lithium (which are provided as examples of other kit combinations of the present invention), the predetermined dosing regimen is synchronously administering doses of deuterated gaboxadol and lithium. may include The predetermined dosing regimen is that the dosage of deuterated gaboxadol and lithium, or a pharmaceutically acceptable salt of one or both of these compounds, is administered in the morning, for example between 6:00 am or between about 6:00 am and 9:00 am. is administered in the afternoon, eg, at 12:00 pm (noon) or between about 12:00 pm and 3:00 pm, in the evening, eg, at 6:00 pm or between about 6:00 pm and 9:00 pm, or later Dosing can be provided in the evening, for example at 12:00 am (midnight).

A kit may include a housing configured to organize dosage forms according to a predetermined dosing regimen. For example, the housing can be configured to organize a plurality of dosage forms into a morning dosage form and an evening dosage form. In some variations, the housing may be configured to organize a plurality of deuterated gaboxadol and lithium dosage forms according to a rapidly or progressively decreasing dosing regimen. In another variation, the housing can be configured to organize the deuterated gaboxadol and lithium dosage forms according to the day of the week to be taken.

A kit may include a housing configured to organize dosage forms according to a predetermined dosing regimen. For example, the housing can be configured to organize a plurality of dosage forms into a morning dosage form and an evening dosage form. In some variations, the housing may be configured to organize a plurality of dosage forms according to a rapid or progressively decreasing dosing regimen. In another variation, the housing can be configured to organize the dosage forms according to the day of the week to be taken. Kits can also be tailored to treat specific bipolar conditions or subtypes. For example, the kit may be tailored to treat bipolar I disorder, bipolar II disorder, mixed bipolar disorder, rapid-recycling bipolar disorder, acute mania, drug-induced mania, hypomania, cyclothymia, or combinations thereof. there is.

Embodiments of the present invention

One aspect of the present invention is 4,4; 5,5; 7,7; 4,4,5,5; 4,4,7,7; 5,5,7,7; and a ring carbon deuterated gaboxadol which is a deuterated gaboxadol at a ring carbon position selected from the group consisting of 4,4,5,5,7,7.

One aspect of the present invention is 4,4; 5,5; 7,7; 4,4,5,5; 4,4,7,7; 5,5,7,7; and 4,4,5,5,7,7; ring carbon deuterated gaboxadol, which is a deuterated gaboxadol at a ring carbon position; and a pharmaceutically acceptable carrier.

One aspect of the invention is a method for reducing the risk of suicide and/or achieving rapid-acting relief of depressive symptoms, the method comprising first treatment with a pharmaceutical composition comprising cyclic carbon deuterated gaboxadol. to a patient in need thereof in an amount sufficient to reduce the risk of suicide and/or rapidly relieve depressive symptoms, and optionally a second pharmaceutical composition comprising a cyclic carbon deuterated gaboxadol. administering the treatment within less than 6 hours immediately after administration of the first treatment, and if the patient experiences a recurrence of suicidal risk and/or depressive symptoms, further treatment with a pharmaceutical composition comprising cyclic carbon deuterated gaboxadol , administering at least 48 hours after the first treatment.

A preferred embodiment of this aspect is an additional treatment of a pharmaceutical composition comprising cyclic carbon deuterated gaboxadol is administered at least every 3, 4, 5, 6 or 7 days after administration of the first treatment.

A preferred embodiment of this aspect is that a second treatment of a pharmaceutical composition comprising cyclic carbon deuterated gaboxadol is administered if the patient's neurological tests demonstrate an insufficient response within 180 minutes immediately after administration of the first treatment. will be.

A preferred embodiment of this aspect is an inadequate response is an increase in electroencephalogram (EEG) power density of less than 30% relative to baseline within 180 minutes after the first administration.

A preferred embodiment of this aspect is one in which the electroencephalogram (EEG) power density is calculated in the range of 0.25-8.0 Hz.

A preferred embodiment of this aspect is one in which the electroencephalogram (EEG) power density is calculated in the range of 4.75-8.0 Hz.

A preferred embodiment of this aspect is an inadequate response is a whole head magnetoencephalography (MEG) planar durometer increase of less than +3 in combined delta, theta and alpha activity within 180 minutes after administration of the first treatment.

A preferred embodiment of this aspect is wherein the method provides an amelioration of at least one symptom of suicide risk selected from the group consisting of suicidal ideation, acute suicidal tendencies, recurrent thoughts of death, suicidal behavior, and/or suicide attempt. is to do

A preferred embodiment of this aspect is that the patient is further diagnosed with a condition selected from suicidal ideation, acute suicidal tendencies, risk of self harm, and/or treatment resistant depression.

A preferred embodiment of this aspect is that the patient has not previously been treated with, is not currently being treated with, or does not respond to an anti-depressive treatment.

A preferred embodiment of this aspect is wherein the administration of the first treatment comprises administering a pharmaceutical composition comprising from about 1 mg to about 300 mg of cyclic carbon deuterated gaboxadol.

A preferred embodiment of this aspect is wherein the administration of the first treatment comprises administering a pharmaceutical composition comprising from about 1 mg to about 20 mg of cyclic carbon deuterated gaboxadol.

A preferred embodiment of this aspect is wherein the administration of the first treatment comprises administering a pharmaceutical composition comprising from about 5 mg to about 10 mg of cyclic carbon deuterated gaboxadol.

A preferred embodiment of this aspect is that the first treatment is administered in an oral dosage form.

A preferred embodiment of this aspect is that the oral dosage form is an orally disintegrating form.

A preferred embodiment of this aspect is that the first treatment is administered intranasally.

Preferred embodiments of this aspect are ketamine, SAGE-217, allopregnanolone, ganaxolone, alphadolone, alpaxolone, hydroxydione, minaxolone, pregnanolone, renanolone and other pregnanc neurosteroids, AV- 101 (L-4-chlorokynurenine), rapastinel (GLYX-13), MGS0039, LY-341,495, MK-801 (dizosylpine), Ro 25-6981, lislenemdaz (CERC-301, MK- 0657), afimostinel (NRX-1074), ranisemin (AZD6765), traxoprodil (CP-101606), (2R,6R)-hydroxynorketamine, deagglomerating agent (INN) (RG1578, RO4995819), Memantine, tiagabine, gaboxadol, clozapine, [2-amino-4-(2,4,6-trimethylbenzylamino)-phenyl]-carbamic acid ethyl ester (AA29504) and pharmaceutically acceptable salts thereof It further comprises administering a pharmaceutical composition comprising cyclic carbon deuterated gaboxadol to the patient before, after, or concurrently with any one of the first treatment.

A preferred embodiment of this aspect is wherein the first treatment comprises the simultaneous administration of a synergistic dose of a pharmaceutical composition comprising a ring carbon deuterated gaboxadol with a synergistic dose of ketamine.

A preferred embodiment of this aspect is a synergistic dose of cyclic carbon deuterated gaboxadol of less than about 10 mg.

A preferred embodiment of this aspect is a synergistic dose of ketamine of less than about 10 mg.

One aspect of the present invention is an improvement of a method for reducing the risk of suicide and/or achieving rapid-acting relief of depressive symptoms, the method comprising a first treatment with a pharmaceutical composition comprising gaboxadol, comprising: Administering to a patient in need thereof in an amount sufficient to reduce the risk of suicide and/or rapidly relieve depressive symptoms, and optionally a second treatment of a pharmaceutical composition comprising gaboxadol, of the first treatment administering within less than 6 hours immediately after administration, and if the patient experiences a recurrence of suicidal risk and/or depressive symptoms, administering additional treatment with a pharmaceutical composition comprising gaboxadol at least 48 hours after the first treatment wherein the improvement comprises administering a pharmaceutical composition comprising cyclic carbon deuterated gaboxadol at a dosage that is less than about two-thirds of the effective amount of the dosage of gaboxadol.

One aspect of the invention is 4,4; 5,5; 7,7; 4,4,5,5; 4,4,7,7; 5,5,7,7; and a pharmaceutical composition comprising a deuterated gaboxadol at a ring carbon position selected from the group consisting of 4,4,5,5,7,7, a deuterated gaboxadol at a ring carbon and lithium and a pharmaceutically acceptable carrier. am.

One aspect of the present invention is a pharmaceutical composition comprising a combination of compounds, wherein the combination comprises ring carbon deuterated gaboxadol, lithium or a pharmaceutically acceptable salt of one or both of these compounds; The dose of carbon-deuterated gaboxadol is about one-third the dose of non-deuterated gaboxadol required to achieve an equivalent synergistic effect.

A preferred embodiment of this aspect is a pharmaceutical composition wherein the lithium is a substandard daily dose of lithium.

A preferred embodiment of this aspect is a pharmaceutical composition wherein the substandard dosage of lithium, when administered daily to a subject in need thereof, is capable of treating a psychiatric disorder, including bipolar disorder, depression, treatment-resistant depression, and suicidal tendencies. less than the medically recommended dose.

A preferred embodiment of this aspect is a pharmaceutical composition wherein an animal equivalent of a subnormal dose of lithium is ineffective in activating c-fos signaling in the brain of an animal model as determined by pharmacomapping.

A preferred embodiment of this aspect is a pharmaceutical composition wherein the human equivalent of a substandard dose of lithium ranges from about 50 to about 600 mg lithium carbonate/day.

A preferred embodiment of an aspect of the present invention is a pharmaceutical composition wherein gaboxadol has two ring deuterium atoms.

A preferred embodiment of an aspect of the present invention is a pharmaceutical composition wherein gaboxadol has 4 ring deuterium atoms.

A preferred embodiment of an aspect of the present invention is a pharmaceutical composition wherein gaboxadol has 6 ring deuterium atoms.

A preferred embodiment of an aspect of the present invention is a pharmaceutical composition wherein gaboxadol is a mixture of gaboxadol having 2, 4 or 6 deuterium atoms.

A preferred embodiment of an aspect of the present invention is a pharmaceutical composition wherein the lithium is a standard dose of lithium.

A preferred embodiment of an aspect of the invention is a pharmaceutical composition wherein the standard dosage of lithium ranges from about 600 to about 1800 mg of lithium carbonate/day, with a maximum daily dosage of 2400 mg.

A preferred embodiment of an aspect of the present invention is a pharmaceutical composition wherein the deuterated gaboxadol and lithium are formulated in two separate compositions.

A preferred embodiment of an aspect of the present invention is a pharmaceutical composition wherein the combination consists of lithium and deuterated gaboxadol present as pharmaceutically acceptable salts thereof.

One aspect of the present invention is a pharmaceutical composition wherein an animal equivalent dose of lithium and cyclic carbon deuterated gaboxadol administered daily to an animal model in need thereof is: 1) motor (MO), gustatory (GU), Instinctive (VISC), agranular lateral cortex (AI), auditory (SS), auditory, visual (VIS), auditory (AUD), prelimbic (PL) and lower part of the limbic system (ILA), occipital lobe (RSP), body wall (PTL), temporal association (TEa), external olfactory (ECT), internal olfactory (ENT), periorbital (PERI), cutaneous (PIR), and anterior cingulate (ACA) cortex, a wide area including the anterior cingulate (CLA) cortical activation; as well as 2) hippocampal CA1 area, stratified nuclear demarcation striatum (BST), central amygdala (CEA), cortical amygdala (COA), basolateral and basolateral amygdala (BLA and BMA), medial amygdala (MEA), thalamic ventromedial posteromedial nucleus (VPM), subparascapular nucleus (SPF), medial geniculate complex (MG), anterior geniculate nucleus (SGN), nucleus of recombination (RE), rhomboid nucleus (RH), and medial central nucleus of the thalamus (CM) ), paraventricular nucleus, hypothalamic nucleus (PVH), posteromedial nucleus of the hypothalamus (DMH), mammary nucleus (TM), parathalamic nucleus (PSTN) and hypothalamic nucleus (STN), brachial nucleus, lumbar nucleus (LC) , and subcortical activation involving the nucleus of the solitary tract (NTS).

One aspect of the invention is a pharmaceutical composition wherein the ring carbon deuterated gabadoxadol and lithium, when administered daily to a subject in need thereof, are free from the group consisting of bipolar disorder, depression, treatment-resistant depression, and acute suicidal tendencies. act synergistically in the treatment of a psychiatric disorder in a selected subject, and the dose of cyclic carbon deuterated gaboxadol is about 1 of the amount of non-deuterated gaboxadol required to achieve an equivalent synergistic effect. /3.

A preferred embodiment of this aspect is one in which treatment of a subject's mental disorder is effective to improve a score on at least one mental state assessment scale specific to bipolar disorder, depression, treatment-resistant depression, or suicidal tendencies.

A preferred embodiment of an aspect of the present invention is a pharmaceutical composition wherein the ring carbon deuterated gaboxadol and lithium, when administered to a subject diagnosed with bipolar depression, unipolar depression, or treatment-resistant depression, cause a decrease in the subject's Montgomery-Asberg It is synergistically effective in increasing depression rating scale (MADRS) scores.

A preferred embodiment of an aspect of the invention is a pharmaceutical composition wherein the ring carbon deuterated gaboxadol and lithium, when administered to a subject in need thereof, are specific for bipolar disorder, depression, treatment-resistant depression, or suicidal tendencies. is synergistically effective in increasing scores on at least one mental state assessment scale.

A preferred embodiment of an aspect of the invention is a pharmaceutical composition wherein the lithium is in an amount sufficient to maintain a serum level of lithium in a subject in the range of about 0.4 to about 1.2 mmol/L when administered daily to a subject in need thereof. am.

A preferred embodiment of an aspect of the invention is a pharmaceutical composition wherein the lithium is in an amount sufficient to maintain a serum level of lithium in a subject in the range of about 0.2 to about 0.8 mmol/L when administered daily to a subject in need thereof. am.

A preferred embodiment of an aspect of the present invention is a pharmaceutical composition, wherein the pharmaceutical composition is in the form of a single tablet for oral consumption.

A preferred embodiment of an aspect of the present invention is a pharmaceutical composition, wherein the pharmaceutical composition is in the form of a controlled release dosage form.

A preferred embodiment of an aspect of the present invention is a pharmaceutical composition further comprising one or more inert pharmaceutically acceptable excipients.

A preferred embodiment of an aspect of the present invention is a pharmaceutical composition wherein the pharmaceutical composition is a single dosage form having separate compartments for lithium and cyclic carbon deuterated gaboxadol or a pharmaceutically acceptable salt of one or both of these compounds. It is a unit form.

One aspect of the present invention is a kit comprising the pharmaceutical composition of an aspect of the present invention.

One aspect of the invention is a method for treating a subject in need thereof comprising administering a pharmaceutical composition of any aspect of the invention.

A preferred embodiment of this aspect is that the subject has been diagnosed with a mental disorder.

A preferred embodiment of this aspect is that the mental disorder is selected from bipolar disorder, depression, treatment resistant depression, or acute suicidal tendencies.

A preferred embodiment of this aspect is that the pharmaceutical composition is used to treat nephrotoxicity, nephropathy insipidus, chronic kidney disease, diarrhea, tremor, increased thirst, increased urination, vomiting, weight gain, poor memory, poor concentration, drowsiness, muscle weakness, hair loss, acne and and reducing an adverse side effect selected from the group consisting of hypothyroidism.

One aspect of the present invention is a method for treating a human diagnosed with bipolar disorder, depression, or acute suicidal tendencies, the method comprising:

Doses ranging from about 5 to about 300 mg/day of the cyclic carbon deuterated gaboxadol of the carbon synergistic combination,

a) a dosage of about 50 mg to about 1800 mg lithium carbonate; or

b) about 0.8 mg/kg to about 30 mg/kg lithium carbonate; or

c) an amount sufficient to achieve a lithium serum concentration of about 0.2 to 1.2 mmol/L.

The step of administering between lithium and the same period of

including,

wherein the combined dose of cyclic carbon deuterated gaboxadol and lithium is administered at least once per day.

One aspect of the present invention is a method for treating a human diagnosed with an acute form of bipolar disorder, depression, or suicidal tendencies, the method comprising:

Doses ranging from about 5 mg to about 50 mg/day of the cyclic carbon deuterated gaboxadol of the carbon synergistic combination,

a) a dosage of about 50 mg to about 900 mg lithium carbonate/day; or

b) an amount sufficient to achieve a lithium serum concentration of about 0.2 to 1.0 mmol/L.

The step of administering between lithium and the same period of

including,

wherein the combined dose of cyclic carbon deuterated gaboxadol and lithium is administered at least once per day.

One aspect of the present invention is a method for treating a patient diagnosed with a chronic form of bipolar disorder, depression, or suicidal tendencies, the method comprising:

Doses ranging from about 5 mg to about 30 mg/day of the cyclic carbon deuterated gaboxadol of the carbon synergistic combination,

a) a dosage of about 50 mg to about 600 mg lithium carbonate; or

b) an amount sufficient to achieve a lithium serum concentration of about 0.2 to 0.8 mmol/L.

The step of administering between lithium and the same period of

including,

wherein the combined dose of cyclic carbon deuterated gaboxadol and lithium is administered at least once per day.

One aspect of the present invention is an elevation of cyclic carbon deuterated gaboxadol and lithium, or a pharmaceutically acceptable salt of one or both of these compounds, for reducing one or a symptom of bipolar disorder, depression, or suicidal tendencies. It is the use of functional combinations.

One aspect of the present invention relates to the pharmaceutical use of cyclic carbon deuterated gaboxadol and lithium, or one or both of these compounds, in the manufacture of a medicament for reducing one or the symptoms of bipolar disorder, depression, or suicidal tendencies. It is the use of synergistic combinations of acceptable salts.

A first aspect is a cyclic carbon deuterated gaboxadol compound of formula (I) or a pharmaceutically acceptable salt thereof,

(I)

(I)

In the above formula,

R4, R4', R5, R5', R7 and R7' are independently H or D;

At least one of R4, R4', R5, R5', R7 and R7' is D.

A first preferred embodiment of the first aspect is a compound having an incorporation percentage of deuterium of at least 1%.

A second preferred embodiment of the first aspect is a compound wherein if none of R4, R4', R5 and R5' is H, neither R7 nor R7' is D.

A third preferred embodiment of the first aspect is a compound wherein, when R4, R4', R5 and R5' are all D, then at least one of R7 and R7' is D.

A fourth preferred embodiment of the first aspect are compounds wherein all of R4, R4', R5, R5', R7 and R7' are D.

A second aspect is a composition comprising at least one cyclic carbon deuterated gaboxadol compound of formula (I):

(I)

(I)

In the above formula,

R4, R4', R5, R5', R7 and R7' are independently H or D;

At least 1% of the compounds have D in one or more of R4, R4', R5, R5', R7 and R7', optionally at least 1% of the compounds have R4, R4', R5, R5', R7 and R7 ' has a D in all.

A first preferred embodiment of the second aspect is a composition wherein at least 10% of the compounds have D at one or more of R4, R4', R5, R5', R7 and R7'.

A second preferred embodiment of the second aspect is a composition in which at least 10% of the compounds have D at three or more of R4, R4', R5, R5', R7 and R7'.

A third preferred embodiment of the second aspect is a composition wherein at least 10% of the compounds have D at 5 or more of R4, R4', R5, R5', R7 and R7'.

A fourth preferred embodiment of the second aspect is a composition in which at least 70% of the compounds have D in at least 5 of R4, R4', R5, R5', R7 and R7'.

A fifth preferred embodiment of the second aspect is a composition in which at least 90% of the compounds have D in at least 5 of R4, R4', R5, R5', R7 and R7'.

A sixth preferred embodiment of the second aspect is a composition in which at least 75% of the compounds have D in all of R4, R4', R5, R5', R7 and R7'.

A seventh preferred embodiment of the second aspect is a composition comprising at least two different compounds of formula (I).

A third aspect is a pharmaceutical composition comprising a compound of any one of the above aspects and embodiments and a pharmaceutically acceptable carrier.

A first preferred embodiment of the third aspect is the pharmaceutical composition in oral dosage form.

A more preferred embodiment of the third aspect is the pharmaceutical composition of the first preferred embodiment of the third aspect which is a tablet.

A more preferred embodiment of the third aspect is the pharmaceutical composition of the first preferred embodiment of the third aspect, wherein the oral dosage form is an orally disintegrating form.

A second preferred embodiment of the third aspect is a pharmaceutical composition comprising from about 1 mg to about 300 mg of the compound.

A third preferred embodiment of the third aspect is a pharmaceutical composition comprising from about 50 mg to about 100 mg of the compound.

A fourth preferred embodiment of the third aspect is a pharmaceutical composition comprising about 50 mg, about 75 mg, or about 100 mg of the compound.

A fifth preferred embodiment of the third aspect is a pharmaceutical composition comprising from about 25 mg to about 50 mg of the compound.

A sixth preferred embodiment of the third aspect is a pharmaceutical composition comprising from about 10 mg to about 30 mg of the compound.

A fourth aspect comprises (a) a compound of any one of the first or second embodiments; (b) lithium, ketamine, AXS-05 (a fixed combination of dextromethorphan and bupropion), SAGE-217, allopregnanolone, ganaxolone, alphadolone, alpaxolone, hydroxydione, minaxolone, pregna Nolon, Lenolone, AV-101 (L-4-chlorokynurenine), Rapastinel (GLYX-13), MGS0039, LY-341,495, MK-801 (dizosylpine), Ro 25-6981, lislenemdaz (CERC-301, MK-0657), afimostinel (NRX-1074), ranisemin (AZD6765), traxoprodil (CP-101606), (2R,6R)-hydroxynorketamine, deagglomerating agent (INN ) (RG1578, RO4995819), memantine, tiagabine, clozapine and [2-amino-4-(2,4,6-trimethylbenzylamino)-phenyl]-carbamic acid ethyl ester (AA29504) at least one other compound; and (c) a pharmaceutically acceptable carrier.

A first preferred embodiment of the fourth aspect is the pharmaceutical composition of the fourth aspect, wherein the at least one other compound is lithium.

A fifth aspect is a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable salt thereof,

(I)

(I)

In the above formula,

R4, R4', R5, R5', R7 and R7' are independently H or D;

R4, R4', R5, R5', R7 and R7' are all D in at least 75% of the compounds.

A first preferred embodiment of the fifth aspect is the pharmaceutical composition wherein at least 95% of the total of all positions R4, R4', R5, R5', R7 and R7' are D.

A second preferred embodiment of the fifth aspect is a pharmaceutical composition wherein up to about 20% of the compound is d5-gaboxadol.

A sixth aspect is a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable salt thereof,

(I)

(I)

In the above formula,

R4, R4', R5, R5', R7 and R7' are independently H or D;

At least three of positions R4, R4', R5, R5', R7 and R7' are D in at least about 10% of the compounds.

A first preferred embodiment of the sixth aspect is the pharmaceutical composition wherein at least three of positions R4, R4', R5, R5', R7 and R7' are D in at least about 50% of the compounds.

A more preferred embodiment of the sixth aspect is the pharmaceutical composition of the first preferred embodiment, wherein at least three of positions R4, R4', R5, R5', R7 and R7' are D in at least about 70% of the compound.

A more preferred embodiment of the sixth aspect is the pharmaceutical composition of the first preferred embodiment, wherein at least three of positions R4, R4', R5, R5', R7 and R7' are D in at least about 95% of the compounds.

A seventh aspect is a method for producing d6-gaboxadol, the method comprising:

(a) treating 3-hydroxypyridine-4-carboxylic acid with deuterium oxide under catalytic hydrogenation conditions to provide 2,3,6-trideuterio-5-hydroxy-pyridine-4-carboxylic acid;

(b) treating 2,3,6-trideuterio-5-hydroxy-pyridine-4-carboxylic acid from step (a) with a methylating agent to obtain methyl 2,3,6-trideuterio-5- providing hydroxy-pyridine-4-carboxylate;

(c) treating the methyl 2,3,6-trideuterio-5-hydroxy-pyridine-4-carboxylate from step (b) with hydroxylamine hydrochloride to obtain 2,3,6-tridew providing terio-5-hydroxy-pyridine-4-carbohydroxamic acid;

(d) treating the 2,3,6-trideuterio-5-hydroxy-pyridine-4-carbohydroxamic acid from step (c) with an activator to obtain 4,5,7-trideuterioisoxa providing zolo[5,4-c]pyridin-3-one;

(e) treating the 4,5,7-trideuterioisooxazolo[5,4-c]pyridin-3-one from step (d) with a bromination agent to obtain 6-benzyl-4,5,7-tri providing deuterio-isoxazolo[5,4-c]pyridin-6-ium-3-ol bromide;

(f) treating the 6-benzyl-4,5,7-trideuterio-isoxazolo[5,4-c]pyridin-6-ium-3-ol bromide from step (e) with a reducing agent; providing 6-benzyl-4,4,5,5,7,7-hexadeuterio-isoxazolo[5,4-c]pyridin-3-ol; and

(g) deprotecting the 6-benzyl-4,4,5,5,7,7-hexadeuterio-isoxazolo[5,4-c]pyridin-3-ol from step (f) above; removing the benzyl group to provide d6-gaboxadol

includes

A first preferred embodiment of the seventh aspect is a method comprising the following steps:

(a) 2,3,6-trideuterio- providing 5-hydroxy-pyridine-4-carboxylic acid;

(b) treatment of 2,3,6-trideuterio-5-hydroxy-pyridine-4-carboxylic acid from step (a) with methanol and sulfuric acid at reflux temperature to obtain methyl 2,3,6-tridew providing terio-5-hydroxy-pyridine-4-carboxylate;

(c) treating the methyl 2,3,6-trideuterio-5-hydroxy-pyridine-4-carboxylate from step (b) with hydroxylamine chloride and aqueous sodium hydroxide solution to obtain 2,3,6 -providing trideuterio-5-hydroxy-pyridine-4-carbohydroxamic acid;

(d) treating 2,3,6-trideuterio-5-hydroxy-pyridine-4-carbohydroxamic acid from step (c) with thionyl chloride to obtain 4,5,7-trideuterio-5-hydroxy-pyridine-4-carbohydroxamic acid providing oisoxazolo[5,4-c]pyridin-3-one;

(e) 4,5,7-trideuterioisoxazolo[5,4-c]pyridin-3-one from step (d) is treated with benzyl bromide to obtain 6-benzyl-4,5,7- providing trideuterio-isoxazolo[5,4-c]pyridin-6-ium-3-ol bromide;

(f) 6-benzyl-4,5,7-trideuterio-isoxazolo[5,4-c]pyridin-6-ium-3-ol bromide from step (e) above is mixed with deuterated ethanol and 6-benzyl-4,4,5,5,7,7-hexadeuterio-isoxazolo[5,4-c]pyridine by treatment with sodium deuterated borohydride (NaBD4) in a mixture of deuterium oxides. providing a -3-ol; and

(g) 6-benzyl-4,4,5,5,7,7-hexadeuterio-isoxazolo[5,4-c]pyridin-3-ol from step (f) above, (i ) methyl chloroformate in the presence of an inorganic base followed by hydrobromic acid, or (ii) treatment with deuterated hydrobromic acid to give d6-gaboxadol.

A first preferred embodiment of the seventh aspect is a product of the method of the seventh embodiment.

An eighth aspect is the compound 4,5,7-trideuterioisooxazolo[5,4-c]pyridin-3-one.

A ninth aspect is a treatment for a mental disorder, comprising administering to a human patient in need of such treatment a therapeutically effective amount of the compound of the first aspect, the composition of the second aspect, or the pharmaceutical composition of the third aspect. way to treat

A first preferred embodiment of the ninth aspect is that the mental disorder is depression.

A second preferred embodiment of the ninth aspect is that the mental disorder is major depression.

A third preferred embodiment of the ninth aspect is that the mental disorder is suicidal tendencies.

A fourth preferred embodiment of the ninth aspect is that the mental disorder is treatment resistant depression.

A fifth preferred embodiment of the ninth aspect is that the mental disorder is bipolar disorder.

A sixth preferred embodiment of the ninth aspect is a method wherein the administration is once daily.

A seventh preferred embodiment of the ninth aspect is the method wherein the administration is a daily dose of about 50-100 mg of the compound.

An eighth preferred embodiment of the ninth aspect is the method of the seventh preferred aspect wherein the daily dosage is 50, 75 or 100 mg of the compound.

A tenth preferred embodiment of the ninth aspect is a method wherein the mental disorder is depression.

An eleventh preferred embodiment of the ninth aspect is a method further comprising administering lithium to the patient for treating a mental disorder.

A twelfth preferred embodiment of the ninth aspect is the method of the eleventh preferred embodiment, wherein the compound and lithium are in single oral dosage form.

A thirteenth preferred embodiment of the ninth aspect is the method of the eleventh preferred embodiment, wherein the compound and lithium are separate oral dosage forms.

A fourteenth preferred embodiment of the ninth aspect is the method wherein administration is daily for a first period, followed by a washout period of at least 1 day during which the compound is not administered, followed by daily administration for a second period.

A fifteenth preferred embodiment of the ninth aspect is the method wherein the administration is twice or three times per week.

A sixteenth preferred embodiment of the ninth aspect is the method of the fourteenth or fifteenth preferred embodiment, wherein the daily administration is a daily dose of about 50-100 mg of the compound.

A seventeenth preferred embodiment of the ninth aspect is the method of the twelfth preferred embodiment wherein the daily dosage is 50, 75 or 100 mg of the compound.

An eighteenth preferred embodiment of the ninth aspect is the method of the fourteenth to seventeenth preferred embodiments, wherein the compound is the sole active agent administered to treat said mental disorder.

An eighteenth preferred embodiment of the ninth aspect is the method of the fourteenth to seventeenth preferred embodiments, wherein the mental disorder is bipolar mania.

A nineteenth preferred embodiment of the ninth aspect is the method of any preferred embodiment wherein the compound is d6-gaboxadol.

A tenth aspect is the use of the pharmaceutical composition of the third aspect for treating a mental disorder.

An eleventh aspect is the use of a compound of the first aspect in the manufacture of a medicament.

A twelfth aspect is the use of a compound of the first aspect in the manufacture of a medicament for use in the treatment of a mental disorder.

A thirteenth aspect is a method for treating a subject diagnosed with a mental disorder comprising administering to the subject an effective amount of cyclic carbon deuterated gaboxadol or a pharmaceutically acceptable salt thereof.

A first preferred embodiment of the thirteenth aspect is a method wherein the mental disorder is bipolar disorder.

A second preferred embodiment of the thirteenth aspect is a method wherein the mental disorder is depression.

A third preferred embodiment of the thirteenth aspect is the method wherein the mental disorder is major depression.

A fourth preferred embodiment of the thirteenth aspect is a method wherein the mental disorder is treatment resistant depression and suicidal tendencies.

A fifteenth aspect is a method for treating a subject diagnosed with a mental disorder, comprising administering to the subject an effective amount of a cyclic carbon deuterated gaboxadol compound of formula (I):

In the above formula,

R4, R4', R5, R5', R7 and R7' are independently H or D;

At least one of R4, R4', R5, R5', R7 and R7' is D.

A sixteenth aspect is to treat a subject diagnosed with a mental disorder, comprising administering to the subject an effective amount of a composition comprising at least one cyclic carbon deuterated gaboxadol compound of formula (I) below or a pharmaceutically acceptable salt thereof is a way to do it,

In the above formula,

R4, R4', R5, R5', R7 and R7' are H or D;

At least 1% of the compounds have D at one or more of R4, R4', R5, R5', R7 and R7'.

A first preferred embodiment of the sixteenth aspect is a method wherein at least 10% of the compounds have D at one or more of R4, R4', R5, R5', R7 and R7'.

A second preferred embodiment of the sixteenth aspect is a method wherein at least 10% of the compounds have D at 3 or more of R4, R4', R5, R5', R7 and R7'.

A third preferred embodiment of the sixteenth aspect is a method wherein at least 10% of the compounds have D at 5 or more of R4, R4', R5, R5', R7 and R7'.

A fourth preferred embodiment of the sixteenth aspect is a method wherein at least 70% of the compounds have D at 5 or more of R4, R4', R5, R5', R7 and R7'.

A fifth preferred embodiment of the sixteenth aspect is a method wherein at least 90% of the compounds have D at 5 or more of R4, R4', R5, R5', R7 and R7'.

A sixth preferred embodiment of the sixteenth aspect is the method wherein at least 75% of the compounds have D in all of R4, R4', R5, R5', R7 and R7'.

A seventh preferred embodiment of the sixteenth aspect is a method wherein the composition comprises at least two different compounds of formula (I).

An eighth preferred embodiment of the sixteenth aspect is a method wherein the cyclic carbon deuterated gaboxadol is provided in a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

A ninth preferred embodiment of the sixteenth aspect is the method of the eighth preferred embodiment wherein the mental disorder is bipolar disorder.

A tenth preferred embodiment of the sixteenth aspect is the method of the eighth preferred embodiment, wherein the mental disorder is depression.

An eleventh preferred embodiment of the sixteenth aspect is the method of the eighth preferred embodiment, wherein the mental disorder is treatment resistant depression.

A twelfth preferred embodiment of the sixteenth aspect is the method of the eighth preferred embodiment wherein the mental disorder is suicidal tendencies.

A thirteenth preferred embodiment of the sixteenth aspect is the method of the ninth to twelfth preferred embodiments, wherein the pharmaceutical composition is in oral dosage form.

A fourteenth preferred embodiment of the sixteenth aspect is the method of the twelfth preferred embodiment, wherein the pharmaceutical composition comprises from about 1 mg to about 300 mg of a compound of Formula I.

A fifteenth preferred embodiment of the sixteenth aspect is the method of the twelfth preferred embodiment, wherein the pharmaceutical composition comprises from about 50 mg to about 100 mg of a compound of Formula I.

A sixteenth preferred embodiment of the sixteenth aspect is the method of the twelfth preferred embodiment, wherein the pharmaceutical composition comprises from about 25 mg to about 50 mg of a compound of Formula I.

A seventeenth preferred embodiment of the sixteenth aspect is the method of the twelfth preferred embodiment, wherein the pharmaceutical composition comprises from about 10 mg to about 30 mg of a compound of Formula I.

An eighteenth preferred embodiment of the sixteenth aspect is the method of the ninth to twelfth preferred embodiments, wherein the effective amount comprises an amount sufficient to rapidly reduce the risk of suicide, bipolar disorder, and/or depressive symptoms.

A nineteenth preferred embodiment of the sixteenth aspect is the method of the eighteenth preferred embodiment, further comprising administering a second pharmaceutical composition comprising a ring carbon deuterated gaboxadol within less than 6 hours immediately after the previous administering step.

A twentieth preferred embodiment of the sixteenth aspect relates to the administration of a second pharmaceutical composition comprising cyclic carbon deuterated gaboxadol after a determination step in which the patient's neurological tests demonstrate an insufficient response within about 180 minutes immediately following the previous administration step. This is the method of the 19th preferred embodiment.

A 21st preferred embodiment of the 16th aspect is the method of the 20th preferred embodiment wherein the insufficient response is an increase in electroencephalogram (EEG) power density of less than 30% relative to baseline within about 180 minutes after the previous administration step.

A 22nd preferred embodiment of the 16th aspect is the method of the 21st preferred embodiment wherein the electroencephalogram (EEG) power density is calculated in the range of 0.25-8.0 Hz.

A twenty-third preferred embodiment of the sixteenth aspect is the method of the twenty-first preferred embodiment wherein the electroencephalogram (EEG) power density is calculated in the range of 4.75-8.0 Hz.

A 24 preferred embodiment of aspect 16 is a 20 preferred embodiment wherein the insufficient response is a whole head magnetoencephalography (MEG) planar durometer increase of less than +3 in combined delta, theta and alpha activity within about 180 minutes after the previous administration step. It is a method of an embodiment.

A twenty-fifth preferred embodiment of the sixteenth aspect is the method wherein the effective amount is administered daily.

A twenty-sixth preferred embodiment of the sixteenth aspect is the method wherein an effective amount is administered intermittently, spaced apart by a drug washout period of at least one day in which deuterated gaboxadal is not administered.

A seventeenth aspect relates to a first pharmaceutical composition comprising an effective amount of cyclic carbon deuterated gaboxadol or a pharmaceutically acceptable salt thereof, and lithium, ketamine, SAGE-217, allopregnanolone, ganaxolone, alphadolone, Alfaxolone, hydroxydione, minaxolone, pregnanolone, renanolone and other pregnane neurosteroids, AV-101 (L-4-chlorokynurenine), rapastinel (GLYX-13), MGS0039, LY-341,495 , MK-801 (dizocilpine), Ro 25-6981, lislenemdaz (CERC-301, MK-0657), afimostinel (NRX-1074), ranisemin (AZD6765), traxoprodil (CP- 101606), (2R,6R)-hydroxynorketamine, deagglomerating agent (INN) (RG1578, RO4995819), memantine, tiagabine, gaboxadol, clozapine and [2-amino-4-(2,4,6 -trimethylbenzylamino)-phenyl]-carbamic acid ethyl ester (AA29504), AXS-05 (a fixed combination of dextromethorphan and bupropion) and pharmaceutically acceptable salts thereof, comprising an agent selected from the group consisting of A method for treating a subject diagnosed with a mental disorder comprising administering to the subject a second pharmaceutical composition comprising:

A first preferred embodiment of the seventeenth aspect is a method wherein the active agent in the second pharmaceutical composition is ketamine.

A second preferred embodiment of the seventeenth aspect is the method of the first preferred embodiment wherein the effective amount of cyclic carbon deuterated gaboxadol or a pharmaceutically acceptable salt thereof is about 20 mg or less.

A third preferred embodiment of the seventeenth aspect is the method of the first preferred embodiment wherein the effective amount of ketamine is about 10 mg or less.

An eighteenth embodiment is a method for treating a subject diagnosed with a mental disorder comprising administering at least once per day a combination of cyclic carbon deuterated gaboxadol and lithium, wherein lithium is

(a) an amount of about 50 mg to about 1800 mg lithium carbonate; or

(b) an amount of about 0.8 mg/kg to about 30 mg/kg lithium carbonate; or

(c) an amount sufficient to achieve a lithium serum concentration of about 0.2 to 1.2 mmol/L.

is dosed with

A first preferred embodiment of the eighteenth aspect is wherein the cyclic carbon deuterated gaboxadol is administered in an amount of about 10 mg to about 100 mg, and the lithium is (a) in an amount of about 50 mg to about 900 mg lithium carbonate, or (b ) in an amount sufficient to achieve a lithium serum concentration of 0.2 to 1.0 mmol/L.

A second preferred embodiment of the eighteenth aspect is that the cyclic carbon deuterated gaboxadol is administered in an amount of about 15 mg to about 50 mg, and the daily dosage of lithium is in an amount of about 50 mg to about 600 mg lithium carbonate, or ( b) in an amount sufficient to achieve a lithium serum concentration of about 0.2 to 0.8 mmol/L.

A third preferred embodiment of the eighteenth aspect is a method wherein the mental disorder is bipolar disorder.

A fourth preferred embodiment of the eighteenth aspect is the method wherein the mental disorder is depression.

A fifth preferred embodiment of the eighteenth aspect is the method wherein the mental disorder is treatment resistant depression.

A sixth preferred embodiment of the eighteenth aspect is a method wherein the mental disorder is suicidal tendencies.

A nineteenth aspect is the use of a combination of ring carbon deuterated gaboxadol and lithium, or a pharmaceutically acceptable salt of one or both of these compounds, for the treatment of a psychiatric disorder.

A twentieth embodiment is the use of a combination of ring carbon deuterated gaboxadol and lithium, or a pharmaceutically acceptable salt of one or both of these compounds, in the manufacture of a medicament for the treatment of a mental disorder.

A twenty-first aspect is a pharmaceutical composition comprising a cyclic carbon deuterated gaboxadol of formula (I) or a pharmaceutically acceptable salt thereof and (b) lithium or a pharmaceutically acceptable salt of lithium;

(I)

(I)

In the above formula,

R4, R4', R5, R5', R7 and R7' are independently H or D;

At least one of R4, R4', R5, R5', R7 and R7' is D.

A first preferred embodiment of the twentieth aspect is a pharmaceutical composition wherein the cyclic carbon deuterated gaboxadol is added to the pharmaceutical composition in an amount that is up to about 2/3 of the dosage of non-deuterated gaboxadol required to achieve an equivalent effect. exist.

A second preferred embodiment of the twentieth aspect is the pharmaceutical composition wherein the lithium is present in the pharmaceutical composition in an amount that is a substandard daily dose of lithium.

A third preferred embodiment of the twentieth aspect is medically recommended for the treatment of psychiatric disorders, including bipolar disorder, depression, treatment resistant depression, suicidal tendencies, when subnormal doses of lithium are administered daily to a subject in need thereof. is less than the dose of the pharmaceutical composition of the second preferred embodiment.

A fourth preferred embodiment of the twentieth aspect is the pharmaceutical composition of the first preferred embodiment wherein the dose of cyclic carbon deuterated gaboxadol is less than or equal to 1/3 of the amount of non-deuterated gaboxadol required to achieve an equivalent effect. .

A fifth preferred embodiment of the twentieth aspect is a pharmaceutical composition in the form of a single dosage unit having separate compartments for the lithium and the cyclic carbon deuterated gaboxadol or a pharmaceutically acceptable salt of one or both of these compounds. .

A sixth preferred embodiment of the twentieth aspect is a pharmaceutical composition wherein the cyclic carbon deuterated gaboxadol is d6-gaboxadol.

A seventh preferred embodiment of the twentieth aspect is a kit comprising the pharmaceutical composition of the twentieth aspect.

Example

The examples are presented below for purposes of illustration and to illustrate certain specific embodiments of the present invention. However, the claims are not limited in any way by the embodiments herein. Various changes and modifications to the disclosed embodiments will be readily apparent to those skilled in the art, and such changes and modifications, including but not limited to those relating to the methods of the present invention, may be made without departing from the spirit of the present invention and the scope of the appended claims of the present invention. can

Although the present invention has been described with a certain degree of particularity, it should be understood that this disclosure is completed by way of example only, and that many changes to the details of construction and arrangement of parts may be resorted to without departing from the spirit and scope of the present invention. do.

Any patents, patent applications, publications or other publications identified herein are incorporated herein by reference in their entirety. Any material, or portions thereof, which are said to be incorporated herein by reference but conflict with any prior definitions, statements or other published material expressly set forth herein, are included only to the extent that no conflict arises between the incorporated material and the material of this disclosure. do. In case of conflict between this express disclosure and a document incorporated by reference, this express disclosure will be the controlling disclosure.

Examples 1 to 5: Synthesis of cyclic carbon deuterated gaboxadol

Ring carbon deuterated gaboxadol can be synthesized from a deuterated precursor through a synthetic route that incorporates a deuterium at a specific ring carbon position. For discussion of ring carbon deuterated gaboxadol, the numbering of the isoxazole and pyridine ring positions is shown in FIG. 2 .

Example 1A: D2-Gaboxadol 7,7

Reportedly, one d2-gaboxadol, 4,5,6,7-tetrahydroisoxazolo[5,4- c ]pyridin-3(2 H )-one-7,7- d ₂ is It was synthesized using a synthesis identified in Journal of Labeled Compounds and Radiopharmaceuticals 19(5) 689-702 (1982), incorporated herein by reference. It is not known whether the percentage of deuteration of compounds of Formula I in the composition was achieved by this method.

Example 1B: D2-Gaboxadol 7,7

The titled 4,5,6,7-tetrahydroisoxazolo[5,4- c ]pyridin-3(2 H )-one-7,7- d ₂ (d2-gaboxadol 7,7), Another synthesis of the compound is shown below. The synthesis of d2-gaboxadol 7,7 is shown in the schematic of FIG. 3 .

Reagents and conditions: (a) Boc ₂ O, TEA, THF, room temperature, 3 hours; (b) CH ₂ N ₂ , Et ₂ O, 0° C., 4 hours; (c) HCl, dioxane, 0° C. to room temperature, 1 hour; (d) Acetate buffer (PH = 4), NaNO ₂ , 0° C. to room temperature, 2 hours; (e) D ₂ O, TEA/dioxane, 65° C., 26 hours; (f) HBr (33 wt % in AcOH), 70° C., 1 hour.

a. Synthesis of tert-butyl 3-hydroxy-4,7-dihydroisooxazolo[5,4-c]pyridine-6(5H)-carboxylate (2, Figure 3): 4 in THF (140 mL), Boc ₂ O ₍ 10.64 g, 48.75 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 3 hours. The reaction was poured into water (150 mL) and extracted with EtOAc (100 ml x 3). The combined organics were washed with brine (200 mL x 1), dried over Na ₂ SO ₄ , concentrated, and purified by silica gel chromatography (EA/PE = 1/4) to give the desired product as a white solid (9.2 g, 82% yield). LC/MS (ESI): m/z 241 [M+H] ⁺ .

b. Synthesis of tert-butyl 3-methoxy-4,7-dihydroisoxazolo[5,4-c]pyridine-6(5H)-carboxylate (3, Figure 3): in Et ₂ O (100 mL) To a solution of tert-butyl 3-hydroxy-4,7-dihydroisooxazolo[5,4-c]pyridine-6(5H)-carboxylate (9.2 g, 38.29 mmol) in Et ₂ O (130 mL) A solution of CH ₂ N ₂ (3.22 g, 76.58 mmol, freshly prepared) in 0 °C was added dropwise. The reaction solution was stirred at 0 °C for 4 hours. The reaction mixture was quenched with formic acid (3 mL), the pH of the solution was adjusted to -10 with saturated aqueous NaHCO ₃ (50 mL), and extracted with EtOAc (100 ml x 2). The combined organics were washed with brine (300 mL x 1), dried over Na ₂ SO ₄ , concentrated, and purified by silica gel chromatography (DCM) to give the desired product as a white solid (4.57 g, 47% yield). obtained.

Preparation of Diazomethane: 1-methyl-3-nitro-1-nitrosoguanidine (11.3 g, 76.58 mmol) was partitioned in a solution of aqueous KOH (40%) (90 mL) in Et ₂ O (130 mL). It was added at 0 °C. The mixture was stirred at 0 °C for 30 min. The Et ₂ O layer was used directly.

c. Synthesis of 3-methoxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine (4, Figure 3): tert-butyl 3-methoxy- in dioxane (15 mL) A solution of 4,7-dihydroisoxazolo[5,4-c]pyridine-6(5H)-carboxylate (4.57 g, 17.97 mmol) in HCl (60 mL, 4 N solution of 1,4-dioxane) ) was treated. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and dried in vacuo to give the desired product of HCl salt as a white solid (3.4 g, 100% yield). LC/MS (ESI): m/z 155 [M+H] ⁺ .

d. Synthesis of 3-methoxy-6-nitroso-4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridine (5, Figure 3): Acetate buffer (180 mL, pH = 4) To a solution of 3-methoxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine hydrochloride (3.4 g, 17.94 mmol) in _{NaNO 2} ( 12.4 g, 179.7 mmol) was added dropwise at 0 °C. The resulting reaction was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (100 mL) and extracted with DCM (100 ml x 2). The combined organics were washed with brine (200 mL x 1), dried over Na ₂ SO ₄ and concentrated to give a crude product which was triturated with PE/toluene (10/1) to give the desired product (3.0 g). , 91%) as a yellow solid. LC/MS (ESI): m/z 184 [M+H] ⁺ .

e. Synthesis of 3-methoxy-6-nitroso-4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridine-7,7-d2 (6, Figure 3): Et ₃ N( 5 mL) and 3-methoxy-6-nitroso-4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridine (500 mg, 2.73 mmol) and D ₂ O (547 mg, 27.3 mmol) was stirred at 60 °C for 26 h. The reaction mixture was concentrated to give a crude product which was triturated with PE/toluene (10/1) to give the desired product as a yellow solid (400 mg, 79% yield). ¹ H NMR data (CDCl ₃ ) are consistent with 6 being a mixture of two rotational isomers (about 1/4).

f. Synthesis of 4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridin-7,7-d2-3-ol (7, Figure 3): HBr (8 mL, 33% wt in AcOH ) of 3-methoxy-6-nitroso-4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridine (400 mg, 2.16 mmol) was stirred at 70°C for 1 hour. did The reaction mixture was concentrated, diluted in water (2 mL) and the pH was adjusted to 6.5 with Et ₃ N/EtOH (10%). The mixture was concentrated to give the crude product which was recrystallized from EtOH/H ₂ O (5/1, 5 mL) to give the desired product as a white solid (100 mg, 33% yield).

The % yield of reactants (33% yield) is not directly related to the measure of deuterium incorporation.

Table V: Raw data of FIG. 4

(Evaluation of ¹³ C isotope incorporation is based on ESI-MS analysis of samples of non-deuterated gaboxadol compositions, which peak at approximately 141, 142 and 143 in a ratio of 100 : 7.4 : 0.65 (data not shown). indicated)

Figure 4 shows the composition of 91.35% d2-Gaboxadol calculated from raw data by peak size intensity and relative abundance using electrospray ionization mass spectrometry (Figure 4). In this example, the d2-gaboxadol peak at 143.10 can be quantified (intensity) and converted to the relative abundance set to 100 in this example. The intensities of the other peaks were determined and the relative abundance was established with respect to the largest peak.

The composition may also be described as 99.55% ring carbon deuterated gaboxadol (deuterated gaboxadol) when all species and forms of deuterated gaboxadol are combined and measured in terms of the amount of non-deuterated gaboxadol. can

Example 1C: D2-Gaboxadol 7,7

4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3(2H)-one-7,7 by the scheme shown in FIG. 3 by also adjusting the final two steps as follows. -d ₂ can be synthesized:

e. Synthesis of 3-methoxy-6-nitroso-4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridine-7,7-d2 (6, Figure 3):

3-methoxy-6-nitroso-4,5,6,7- in Et ₃ N (8 mL) and 1,4-dioxane (8 mL) in a flame-dried 45 mL tube equipped with a magnetic stir bar. Tetrahydroisoxazolo[5,4-c]pyridine (600 mg, 3.28 mmol) and D ₂ O (1.31 g, 65.6 mmol) were charged. The tube was quickly sealed with an aluminum cap and the resulting solution was stirred at 85° C. for 24 hours. The reaction mixture was concentrated to give a crude product which was purified by prep-TLC (eluent: 100% of DCM) to give the desired product as a white solid (500 mg, 82.4% yield). ¹ H NMR data (CDCl ₃ ) were consistent with 6 being a mixture of two rotational isomers (about 1/4).

f. Synthesis of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-7,7-d2-3-ol (7, Figure 3):

3-Methoxy-6-nitroso-4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridine (500 mg, 2.7 mmol) in HBr (10 mL, 33% wt in AcOH) The mixture was stirred at 70 °C for 1 hour. The reaction mixture was concentrated, diluted in water (3 mL) and the pH was adjusted to 6.5 with Et ₃ N/EtOH (10%). The mixture was concentrated to give the crude product which was recrystallized from EtOH/H ₂ O (5/1, 5 mL) to give the desired product as a white solid (250 mg, 64.7% yield).

Example 1D: D2-Gaboxadol 5,5

2 at position 5 of the tetrahydro-pyridine ring, designated 4,5,6,7-tetrahydroisooxazolo[5,4- c ]pyridin-3(2 H )-one-5,5- d ₂ Another d2-gaboxadol deuterated with two deuterium atoms is shown below.

This compound can be prepared from methyl 4-aminobutanoate-4,4- d ₂ according to the procedures contained in DeFaveri et al WO 2016/150953. Ethylene glycol-OD ₂ can replace ethylene glycol in the intermediate stage. Methyl 4-aminobutanoate-4,4- d ₂ was prepared by Wang et al. Pyrrolidin-2-one-5,5- d ₂ was obtained by reduction of succinimide with lithium aluminum tetradeuteride following a similar procedure described in WO 2019/144885, followed by DeFaveri et al WO 2016/ 150953 by treatment with acidic methanol.

Example 1E: D2-Gaboxadol 4,4

The third d2-gaboxadol, 4,5,6,7-tetrahydroisooxazolo[5,4- c ]pyridin-3(2 H )-one-4,4- d ₂ is shown below .

This compound was prepared from known methyl 4-aminobutanoate-2,2,3,3- d ₄ (Wang et al. WO 2019/144885) according to the procedures contained in DeFaveri et al WO 2016/150953 can do. Ethylene glycol-OD ₂ can replace ethylene glycol in the intermediate stage.

Example 1F: D2-Gaboxadol 5,5

은 4,4,5,5-가복사돌-D4에 대한 절차에 따라 상업적으로 입수가능하고 알려진(Wheatly and Keay(2007) Journal of Organic Chemistry, 72(19), 7253-7259) 디하이드로-5d-2(3H)-푸라논-5-d)(감마-부티롤락톤-5,5-d₂)로부터 제조할 수 있다.Alternatively, deuterated gaboxadol can be synthesized by the following procedure. For example, gaboxadol- D ₂ phosphorus, 4,5,6,7-tetrahydroisooxazolo[5,4- c ]pyridin-3(2 H )-one-5,5- d ₂

Dihydro-5d, commercially available and known (Wheatly and Keay (2007) Journal of Organic Chemistry, 72(19), 7253-7259) according to the procedure for silver 4,4,5,5-gaboxadol-D4 -2(3H)-furanone-5-d) (gamma-butyrolactone-5,5-d ₂ ).

Example 1G: D2-Gaboxadol 4,4

는 4,4,5,5-가복사돌-D4에 대한 절차에 따라 알려진 디하이드로-4d-2(3H)-푸라논-4-d)(감마-부티롤락톤-4,4-d₂)(Wheatly and Keay(2007) Journal of Organic Chemistry, 72(19), 7253-7259)로부터 제조할 수 있다.Another d2 species, 4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridin-3(2H)-one-4,4-d2

dihydro-4d-2(3H)-furanone-4-d) (gamma-butyrolactone-4,4-d ₂ ) (Wheatly and Keay (2007) Journal of Organic Chemistry, 72(19), 7253-7259).

Example 1H: D2-Gaboxadol

Figure 5 provides potential alternative synthetic routes for d2-gaboxadol, such as d2-gaboxadol 4,4 and d2-gaboxadol 5,5.

Example 2A: D4-Gaboxadol 4,4,5,5

Deuterated gaboxadol can be synthesized with four deuterated atoms located at ring carbon positions. One such d4-gaboxadol is 4,5,6,7-tetrahydroisooxazolo[5,4- c ]pyridin-3( 2H )-one-4,4,5,5- shown below. d is ₄ .

Such compounds can be prepared from known commercially available pyrrolidin-2-one-3,3,4,4,5,5 -d ₆ according to the procedures contained in DeFaveri et al WO 2016/150953. there is. It can also be prepared according to the literature [Kall et al. (2007)]. It is not known if the percent deuteration of the composition was achieved using the method of Kall et. (2007).

Example 2B: D4-Gaboxadol 4,4,7,7

The second d4-gaboxadol is 4,5,6,7-tetrahydroisoxazolo[5,4- c ]pyridin-3( 2H )-one-4,4,7,7- d shown below. is ₄ .

This compound was prepared as 4,5,6,7-tetrahydroisooxazolo[5,4- c ] according to the procedure for 7,7-dideuterium incorporation contained in Krogsgaard-Larsen 1982 publication. pyridin-3(2 H )-one-4,4- d ₂ .

Example 2C: D4-Gaboxadol 5,5,7,7

Another d4-gaboxadol, 4,5,6,7-tetrahydroisoxazolo[5,4- c ]pyridin-3(2 H )-one-5,5,7,7- d4 _is shown below.

This compound was prepared by 4,5,6,7-tetrahydroisooxazolo[5,4- c ]pyridine-3( 2 H )-one-5,5- d ₂ .

Example 2D: D4-Gaboxadol 4,4,7,7

Alternatively, the title compound is 4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridin-3(2H)-one-4,4,5,5,7,7-d6 4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridin-3(2H)-one-4,4-d2 according to procedures included herein for

Example 2E: D4-Gaboxadol 5,5,7,7

는 문헌 [Krogsgaard-Larsen 1982 publication]에 포함된 7,7-이중수소 혼입에 대한 절차에 따라 4,5,6,7-테트라하이드로이소옥사졸로[5,4-c]피리딘-3(2H)-온-5,5-d2로부터 제조할 수 있다.Another species of gaboxadol-D4, 4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridin-3(2H)-one-5,5,7,7-d4

4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridine-3(2H) according to the procedure for 7,7-deuterium incorporation contained in Krogsgaard-Larsen 1982 publication. It can be prepared from -one-5,5-d2.

Example 2F: D4-Gaboxadol 5,5,7,7

Alternatively, the title compound is 4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridin-3(2H)-one-4,4,5,5,7,7-d6 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3(2H)-one-5,5-d2 according to procedures included herein for

Example 2G: D4-Gaboxadol

Figure 6 provides potential alternative synthetic routes for various species of d4-gaboxadol.

Example 3A: D6-Gaboxadol

d6-Gaboxadol 4,5,6,7-tetrahydroisooxazolo[5,4- c ]pyridin- ₃ ( 2H )-one-4,4,5,5,7,7- d6 is shown below.

This compound was prepared by 4,5,6,7-tetrahydroisooxazolo[5,4- c ]pyridine-3( 2 H )-one-4,4,5,5- d ₄ .

Example 3B: D6-Gaboxadol

Figure 7 provides a potential alternative synthesis to d6-gaboxadol.

Example 4: Synthesis of deuterated gaboxadol

All temperatures are in degrees Celsius (°C) and are uncalibrated. Reagent grade chemicals and anhydrous solvents were purchased from commercial sources and were used without further purification unless otherwise noted. The name of the product was determined using the naming software included with the Biovia electronics lab notebook. Silica gel chromatography was performed on a Teledyne Isco instrument using prepackaged disposable SiO ₂ stationary phase columns with UV detection (254 and 280 nm) with eluent flow rates ranging from 15 to 200 mL/min. Reverse-phase preparative HPLC was performed on a C18 column eluting with a gradient of MeCN in H ₂ O (0.03% (NH ₄ ) ₂ CO ₃ / 0.375% NH ₄ OH, high pH) or MeCN in H ₂ O (0.1% HCOOH, low pH). , using UV detection (214 and 254 nm). Analytical HPLC chromatograms were performed using an Agilent 1100 series instrument equipped with a DAD detector (190 nm to 300 nm). Mass spectra were recorded on a Waters Micromass ZQ detector at 130°C. The mass spectrometer was equipped with an electrospray ion source (ESI) operating in positive or negative ion mode and set to scan between m/z 150-750 or m/z 100-750 with a scan time of 0.3 seconds. Products and intermediates were prepared in a high pH buffer gradient (0.03% (NH ₄ ) ₂ CO ₃ / 0.375% NH of 5% to 100% MeCN in H ₂ O over 2.5 minutes at 1.8 mL/min for a 3.5 minute run (B05). ₄ OH), and 5% to 100% of MeCN in H ₂ O over 2.5 min at 2.2 mL/min for a 3.5 min run (A05). was analyzed by HPLC/MS in EVO C18 (5 M, 3.0 x 50 mm) using a low pH buffer gradient of 0.1% HCOOH. ¹ H NMR spectra were recorded on a Bruker UltraShield 500 MHz/54 mm instrument (BZH 43/500/70B, D221/54-3209). Chemical shifts are shown at 7.26 ppm for CDCl ₃ , 2.50 for DMSO- d ₆ and 3.31 ppm for CD ₃ OD in ¹ H NMR, for CDCl ₃ in ¹³ C NMR. Reference was made to solvent peaks appearing at 77.16 ppm, 39.52 for DMSO- d ₆ and 49.00 ppm for CD ₃ OD.

4.1. Gaboxadol D ₂₍ d2-Gaboxadol 7,7)

A general reaction scheme for gaboxadol D ₂ (d2-gaboxadol 7,7) is provided in FIG. 8 . The individual reaction steps are preferably achieved as follows.

Ethyl 1-[(4-methoxyphenyl)methyl]-3-oxo-piperidine-4-carboxylate; 3

Triethyl to a solution of ethyl 2-[(4-methoxyphenyl)methylamino]acetate 2 (16.0 g, 71.7 mmol) and ethyl 4-bromobutyrate 1 (22.6 mL, 158 mmol) in dioxane (120 mL) Amine (30.2 mL, 214 mmol) was added. The mixture was heated to reflux for 18 hours. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was diluted with water (200 mL) and the aqueous phase was extracted with EtOAc (3 x 50.0 mL). The combined organic layers were dried (MgSO ₄ ), filtered and concentrated under reduced pressure. To the residue in toluene (150 mL) was added NaOEt (21% in EtOH, 58.1 mL, 156 mmol). The mixture was heated to reflux for 18 hours. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was diluted with water (200 mL) and the aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (80 g cartridge) using a gradient of 0-100% EtOAc in hexanes to give the title compound 3 ( 15.4 g) as an oil in 85% yield over two steps.

4.1.2 Ethyl 2,2-dideuterio-1-[(4-methoxyphenyl)methyl]-3-oxo-piperidine-4-carboxylate; 4 ( FIG . 8 ).

To a solution of ethyl ₁ -[(4-methoxyphenyl)methyl]-3-oxo-piperidine-4-carboxylate 3 (4.00 g, 13.7 mmol) in CDCl 3 (130 mL) was added DBU (8.86 mL, 68.6 mL). mmol) was added. The mixture was heated to reflux for 18 hours. After cooling the mixture to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel chromatography (80 g cartridge) using a gradient of 0-100% EtOAc in hexanes to give the title compound 4 ( 2.00 g) as an oil in 50% yield.

4.1.3 reactions; 10,10-dideuterio-9-[(4-methoxyphenyl)methyl]-1,4-dioxa-9-azaspiro[4.5]decane-6-carboxylic acid; 5 ( FIG . 8 ).

Ethyl 2,2-dideuterio-1-[(4-methoxyphenyl)methyl]-3-oxo-piperidine-4-carboxylate 4 (900 mg, 3.07 mmol) and p in toluene (30.0 mL) To a mixture of -toluenesulfonic acid (26.4 mg, 0.153 mmol) was added 1,2-dideuteriooxyethane (10.7 mL, 184 mmol). The mixture was heated to reflux using a Dean-Stark apparatus for 96 hours. After cooling the mixture to room temperature, Na ₂ CO ₃ Diluted with 1 M aqueous solution (20.0 mL). The aqueous phase was extracted with EtOAc (3 x 20.0 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a 0-100% gradient of EtOAc in hexanes (40 g cartridge) to give the title compound 5 .

4.1.4 reactions; 10,10-dideuterio-9-[(4-methoxyphenyl)methyl]-N-tetrahydropyran-2-yloxy-1,4-dioxa-9-azaspiro[4.5]decane-6- carboxamide; 6 ( FIG . 8 ).

10,10-dideuterio-9-[(4-methoxyphenyl)methyl]-1,4-dioxa-9-azaspiro[4.5]decane-6-carboxylic acid 5 (1.00 g) in DMF (20.0 mL) , 3.23 mmol) and O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (416 mg, 3.55 mmol) at 0 ° C. EDCI * HCl (918 mg, 3.55 mmol) and DMAP (19.7 mg , 0.162 mmol) was added. The mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (120 g cartridge) using a gradient of 0-100% EtOAc in hexanes to give the title compound 6 .

4.1.5 reactions; Ethyl 2,2-dideuterio-1-[(4-methoxyphenyl)methyl]-3-oxo-piperidine-4-carboxylate; Gaboxadol D ₂ ( FIG. 8 ).

10,10-dideuterio-9-[(4-methoxyphenyl)methyl]-N-tetrahydropyran-2-yloxy-1,4-dioxa-9-azaspiro [4.5]decane-6- Carboxamide 6 (1.00 g, 2.48 mmol) was added portionwise to 12N DCl at 0°C. The mixture was heated at 50 °C for 2 h and cooled to room temperature. The pH was adjusted to 7 with an aqueous solution of 2N NaOH and EtOAc (100 mL) was added. The separated aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Deuterated TFA (20 mL) was added to the residue. The mixture was heated at 60° C. for 30 min and then cooled to room temperature. MeOH (50 mL) was added dropwise. The precipitate was filtered and rinsed with MeOH. The residue was purified by preparative-HPLC using 10 mM AmBic pH 10 and MeCN to give the title compound Gaboxadol-D ₂ ,4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine -3(2H)-one-7,7-d2 was obtained.

4.2. Gaboxadol D ₄ (d4-Gaboxadol 4,4,5,5)

A general reaction scheme for gaboxadol D ₄ (d4-gaboxadol 4,4,5,5) is provided in FIG. 9 . The individual reaction steps are preferably achieved as follows.

4.2.1 reactions; ethyl 4-bromo-2,2,3,3,4,4-hexadeuterio-butanoate; 2

HBr (33% in AcOH, 20 mL) was added to EtOH (100 mL) at 0 °C. 3,3,4,4,5,5-hexadeuteriotetrahydrofuran-2-one (5 g, 57.3 mmol). The mixture was heated to reflux for 5 hours. The mixture was distilled under reduced pressure to give the title compound 2 .

4.2.2 reactions; Ethyl 2,2,3,3-tetradeuterio-1-[(4-methoxyphenyl)methyl]-5-oxo-piperidine-4-carboxylate; 4

Ethyl 2-[(4-methoxyphenyl)methylamino]acetate 3 (16.0 g, 71.7 mmol) and ethyl 4-bromo-2,2,3,3,4,4-hexa in dioxane (120 mL) To a solution of deuterio-butanoate 2 (15.9 g, 78.9 mmol) was added triethylamine (30.2 mL, 214 mmol). The mixture was heated to reflux for 18 hours. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was diluted with water (200 mL) and the aqueous phase was extracted with EtOAc (3 x 50.0 mL). The combined organic layers were dried (MgSO ₄ ), filtered and concentrated under reduced pressure. To the residue in toluene (150 mL) was added NaOEt (21% in EtOH, 58.1 mL, 156 mmol). The mixture was heated to reflux for 18 hours. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was diluted with water (200 mL) and the aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (80 g cartridge) using a gradient of 0-100% EtOAc in hexanes to give the title compound 4 .

4.2.3 reactions; 7,7,8,8-tetradeuterio-9-[(4-methoxyphenyl)methyl]-1,4-dioxa-9-azaspiro[4.5]decane-6-carboxylic acid; 5

Ethyl 2,2,3,3-tetradeuterio-1-[(4-methoxyphenyl)methyl]-5-oxo-piperidine-4-carboxylate 4 (900 mg, 3.05 mmol) and p-toluenesulfonic acid (26.1 mg, 0.153 mmol) was added ethylene glycol (11.4 g, 183 mmol). The mixture was heated to reflux using a Dean-Stark apparatus for 96 hours. After cooling the mixture to room temperature, it was diluted with a 1 M aqueous solution of Na ₂ CO ₃ (20.0 mL). The aqueous phase was extracted with EtOAc (3 x 20.0 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a 0-100% gradient of EtOAc in hexanes (40 g cartridge) to give the title compound 5 .

4.2.4 reactions; 7,7,8,8-tetradeuterio-9-[(4-methoxyphenyl)methyl]-N-tetrahydropyran-2-yloxy-1,4-dioxa-9-azaspiro[4.5 ]decane-6-carboxamide; 6

7,7,8,8-Tetradeuterio-9-[(4-methoxyphenyl)methyl]-1,4-dioxa-9-azaspiro[4.5]decane-6- in DMF (20.0 mL) To a mixture of carboxylic acid 5 (1.01 g, 3.23 mmol) and O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (416 mg, 3.55 mmol) at 0° C. EDCI*HCl (918 mg, 3.55 mmol) and DMAP (19.7 mg, 0.162 mmol) were added. The mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (120 g cartridge) using a gradient of 0-100% EtOAc in hexanes to give the title compound 6 .

4.2.5 reactions; 4,4,5,5-tetradeuterio-6,7-dihydroisooxazolo[5,4-c]pyridin-3-one; Gaboxadol D ₄

7,7,8,8-tetradeuterio-9-[(4-methoxyphenyl)methyl]-N-tetrahydropyran-2-yloxy-1,4-dioxa-9-azaspiro[4.5 ] Decane-6-carboxamide 6 (1.01 g, 2.48 mmol) was added portionwise to 12N DCl at 0°C. The mixture was heated at 50 °C for 2 h and cooled to room temperature. The pH was adjusted to 7 using an aqueous solution of 2N NaOH and EtOAc (100 mL). The separated aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Deuterated TFA (20 mL) was added to the residue. The mixture was heated at 60° C. for 30 min and then cooled to room temperature. MeOH (50 mL) was added dropwise. The precipitate was filtered and rinsed with MeOH. The residue was purified by prep-HPLC using 10 mM AmBic pH 10 and MeCN to give the title compound gaboxadol-d ₄ .

Also, the title compound 4,5,6,7-tetrahydroisooxazolo[5,4- c ]pyridin-3(2 H )-one-4,4,5,5- d ₄ was reported by Kall et al .(2007)].

4.3. Gaboxadol D ₆

A general reaction scheme for gaboxadol D ₆ is provided in FIG. 10 . The individual reaction steps are preferably achieved as follows.

4.3.1 reactions; Ethyl 2,2,3,3,6,6-hexadeuterio-1-[(4-methoxyphenyl)methyl]-5-oxo-piperidine-4-carboxylate; 2

Ethyl 2,2,3,3-tetradeuterio-1-[(4-methoxyphenyl)methyl]-5-oxo-piperidine-4-carboxylate 1 (4.05 g in CDCl ₃ (130 mL) , 13.7 mmol) was added DBU (8.86 mL, 68.6 mmol). The mixture was heated to reflux for 18 hours. After cooling the mixture to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel chromatography (80 g cartridge) using a gradient of 0-100% EtOAc in hexanes to give the title compound 2 (2.00 g).

4.3.2 reactions; 7,7,8,8,10,10-hexadeuterio-9-[(4-methoxyphenyl)methyl]-1,4-dioxa-9-azaspiro[4.5]decane-6-carboxylic acid; 3

Ethyl 2,2,3,3,6,6-hexadeuterio-1-[(4-methoxyphenyl)methyl]-5-oxo-piperidine-4-carboxylate 2 in toluene (30.0 mL) (913 mg, 3.07 mmol) and p-toluenesulfonic acid (26.4 mg, 0.153 mmol) was added 1,2-dideuteriooxyethane (10.7 mL, 184 mmol). The mixture was heated to reflux using a Dean-Stark apparatus for 96 hours. After cooling the mixture to room temperature, it was diluted with a 1 M aqueous solution of Na ₂ CO ₃ (20.0 mL). The aqueous phase was extracted with EtOAc (3 x 20.0 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a 0-100% gradient of EtOAc in hexanes (40 g cartridge) to give the title compound 3 .

4.3.3 reactions; 7,7,8,8,10,10-hexadeuterio-9-[(4-methoxyphenyl)methyl]-N-tetrahydropyran-2-yloxy-1,4-dioxa-9- azaspiro[4.5]decane-6-carboxamide; 4

7,7,8,8,10,10-hexadeuterio-9-[(4-methoxyphenyl)methyl]-1,4-dioxa-9-azaspiro[4.5] in DMF (20.0 mL) EDCI* HCl (918 mg , 3.55 mmol) and DMAP (19.7 mg, 0.162 mmol) were added. The mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (120 g cartridge) using a gradient of 0-100% EtOAc in hexanes to afford the title compound 4 .

4.3.4 reactions; 4,4,5,5,7,7-hexadeuterio-6H-isoxazolo[5,4-c]pyridin-3-one; Gaboxadol D ₆

7,7,8,8,10,10-hexadeuterio-9-[(4-methoxyphenyl)methyl]-N-tetrahydropyran-2-yloxy-1,4-dioxa-9- Azaspiro[4.5]decane-6-carboxamide 4 (1.02 g, 2.48 mmol) was added portionwise to 12N DCl at 0°C. The mixture was heated at 50 °C for 2 h and cooled to room temperature. The pH was adjusted to 7 with an aqueous solution of 2N NaOH and EtOAc (100 mL) was added. The separated aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Deuterated TFA (20 mL) was added to the residue. The mixture was heated at 60° C. for 30 min and then cooled to room temperature. MeOH (50 mL) was added dropwise. The precipitate was filtered and rinsed with MeOH. The residue was purified by preparative-HPLC using 10 mM AmBic pH 10 and MeCN to give the title compound Gaboxadol-D ₆ ,4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine- 3(2H)-one-4,4,5,5,7,7-d6 was obtained.

Example 5: Synthesis of deuterated gaboxadol d6 (i.e., d6-gaboxadol)

All temperatures are in degrees Celsius (°C) and are uncalibrated. Reagent grade chemicals and anhydrous solvents were purchased from commercial sources and were used without further purification unless otherwise stated. The name of the product was determined using the naming software included with the Biovia electronics lab notebook. Silica gel chromatography was performed on a Teledyne ISCO instrument using prepackaged disposable SiO ₂ stationary phase columns with UV detection (254 and 280 nm) with eluent flow rates ranging from 15 to 200 mL/min. Reverse-phase preparative HPLC was performed on a C18 column eluting with a gradient of MeCN in H ₂ O (0.03% (NH ₄ ) ₂ CO ₃ / 0.375% NH ₄ OH, high pH) or MeCN in H ₂ O (0.1% HCOOH, low pH). , using UV detection (214 and 254 nm). Analytical HPLC chromatograms were performed using an Agilent 1100 series instrument equipped with a DAD detector (190 nm to 300 nm). Mass spectra were recorded on a Waters Micromass ZQ detector at 130°C. The mass spectrometer was equipped with an electrospray ion source (ESI) operating in positive or negative ion mode and set to scan between m/z 150-750 or m/z 100-750 with a scan time of 0.3 seconds. Products and intermediates were prepared in a high pH buffer gradient (0.03% (NH ₄ ) ₂ CO ₃ / 0.375% NH of 5% to 100% MeCN in H ₂ O over 2.5 minutes at 1.8 mL/min for a 3.5 minute run (B05). ₄ OH), and low pH from 5% to 100% of MeCN in H ₂ O over 2.5 min at 2.2 mL/min for a 3.5 min run (A05). Analyzed by HPLC/MS in EVO C18 (5 M, 3.0 x 50 mm) using a buffer gradient (0.1% HCOOH). ¹ H NMR spectra were recorded on a Bruker Ultrashield 500 MHz/54 mm instrument (BZH 43/500/70B, D221/54-3209). Chemical shifts are shown at 7.26 ppm for CDCl ₃ , 2.50 for DMSO- d ₆ and 3.31 ppm for CD ₃ OD in ¹ H NMR, for CDCl ₃ in ¹³ C NMR. Reference was made to solvent peaks appearing at 77.16 ppm, 39.52 for DMSO- d ₆ and 49.00 ppm for CD ₃ OD.

Synthetic scheme for d6-gaboxadol

A schematic for this synthesis can be seen in FIG. 11 .

5.1.1 2,3,6-Trideuterio-5-hydroxy-pyridine-4-carboxylic acid; 2 ( FIG . 11 )

In a high-pressure stainless-steel vessel, 3-hydroxypyridine-4-carboxylic acid 1 (5.0 g, 35.9 mmol), 10 wt% Pt/C (6.31 g, 3.23 mmol) and 10 wt% Pd/C (1.15 g, 1.08 mmol) mmol), then deuterium oxide (175 mL, 9.70 mol) was charged. After bubbling the reaction mixture with H ₂ for 5 min, the apparatus was sealed and the reaction was stirred at 155° C. for 16 h. After cooling the mixture to room temperature, it was degassed with N ₂ for 5 min. An aqueous solution of 1N HCl (250 mL) was added and the mixture was stirred for 1 hour. The mixture was filtered on celite and washed with 1M HCl in MeOH (3 x 100 mL). The filtrate was concentrated under reduced pressure to give the title compound 2 (6 g) as a solid, which was used in the next step without further purification.

5.1.2 methyl 2,3,6-trideuterio-5-hydroxy-pyridine-4-carboxylate; 3 ( FIG . 11 )

To a solution of 2,3,6-trideuterio-5-hydroxy-pyridine-4-carboxylic acid 2 (5.11 g, 36.0 mmol) in MeOH (100 mL) was added concentrated H ₂ SO ₄ (9.63 mL, 0.18 mol). ) was added and the mixture was heated to reflux for 16 hours. After cooling the mixture to room temperature, it was poured into ice-water (500 mL). Solid NaHCO ₃ was added in portions until pH 7 was reached. The aqueous layer was extracted with DCM (3 x 100 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure to give the title compound 3 (2.5 g, 45% yield over 2 steps) as a solid. Compound 3 was identified by ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 3.87(s, 3H). The pyridine ring was 96% deuterated and contained 3% impurity 3A .

5.1.3 2,3,6-trideuterio-5-hydroxy-pyridine-4-carbohydroxamic acid; 4 ( FIG . 11 )

To a suspension of methyl 2,3,6-trideuterio-5-hydroxy-pyridine-4-carboxylate 3 (2.5 g, 16 mmol) in ice-water (15 mL), hydroxylamine hydrochloride (1.67 g, 24 mmol) was added, followed by dropwise addition of 28% w/v NaOH aqueous solution (4 mL). The reaction mixture was stirred at room temperature for 3 hours and then heated at 60°C. At this temperature, concentrated HCl was added dropwise until pH 5.4 was reached. The reaction mixture was then cooled to 0 °C, the pH was adjusted to 4 with concentrated HCl and stirred at 0 °C for 90 minutes. The suspension was filtered, and the solid was washed with water (3 x 10 mL) and dried under reduced pressure to give the title compound 4 (1.90 g, 76% yield) as a solid, which was used in the next step without further purification. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.65 (br s, 1H), 11.38 (br s, 1H), 9.48 (s, 1H) for compound 4 . MS(ESI) [MH] ^- 156.0.

5.1.4 4,5,7-trideuterioisoxazolo[5,4- c ]pyridin-3-one; 5(do11)

A suspension of 2,3,6-trideuterio-5-hydroxy-pyridine-4-carbohydroxamic acid 4 (1.65 g, 10.5 mmol) in pyridine (13 mL) was stirred for 15 min and then cooled to 0 °C. cooled with Thionyl chloride (1.42 mL, 19.4 mmol) was added dropwise while maintaining the temperature below 10° C. and warmed to room temperature upon completion of the addition. The reaction mixture was poured into ice-water (100 mL) with vigorous stirring, then concentrated HCl was added to pH 3. The resulting suspension was stirred for 2 hours at 0° C. and the suspension was filtered. The solid was washed with water (10 mL), EtOH (10 mL) and Et ₂ O (10 mL) and then dried under reduced pressure to give the title compound 5 (680 mg, 47% yield) as a solid, which was further purified. was used in the next step without Compound 5 was identified by ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 12.91 (br s, 1H).

We note that this compound was created specifically to carry out this synthesis.

5.1.5 6-Benzyl-4,5,7-trideuterio-isoxazolo[5,4- c ]pyridin-6-ium-3-ol bromide; 6 ( FIG . 11 )

Benzyl to a solution of 4,5,7-trideuterioisooxazolo[5,4- c ]pyridin-3-one 5 (680 mg, 4.89 mmol) in N-methylpyrrolidone (NMP) (2 ml). Bromide (697 μL, 5.87 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. Acetone (5.00 mL) was added and the resulting solid was filtered, washed with acetone (2 mL), Et ₂ O (5 mL), and dried under pressure to give the title compound 6 (650 mg, 43% yield) as a solid. , which was used in the next step without further purification. Compound 6 was analyzed by ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.58 (d, J = 5.5 Hz, 2H), 7.45 (d, J = 5.6 Hz, 3H), 6.00 (s, 2H). Confirmed by MS(ESI) [M+H] ⁺ 230.1.

5.1.6 6-benzyl-4,4,5,5,7,7-hexadeuterio-isoxazolo[5,4- c ]pyridin-3-ol; 7 ( FIG . 11 )

6-Benzyl-4,5,7-trideuterio-isoxazolo[5,4- c ]pyridin-6-ium-3-ol in ethanol-OD (8 mL) and D ₂ O (8 mL) To a stirred solution of bromide 6 (770 mg, 2.48 mmol) was added NaBD ₄ (208 mg, 4.97 mmol). Note : The reaction mixture foamed upon addition of NaBD ₄ . The mixture was stirred at room temperature for 2 hours. Acetone (1 mL) was added and the volatiles were removed under reduced pressure. The residue was purified by preparative HPLC (BEH column, C18, 30 x 150 mm) using a gradient of 10 mM ammonium formate in water (pH 3.8) and 10-40% MeCN to give the title compound 7 (490 mg, 99% yield) was obtained as a solid. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.35 - 7.31 (m, 4H), 7.30 - 7.24 (m, 1H), 3.67 (s, 2H) for compound 7 . Confirmed by MS(ESI) [M+H] ⁺ 237.1:.

5.1.7 Gaboxadol D6

6-benzyl-4,4,5,5,7,7-hexadeuterio-isoxazolo[5,4- c ]pyridin-3-ol 7 (67 mg, 0.28 mmol) in solution EtOAc (5 mL) ) at room temperature were added DIEA (100 μL, 0.57 mmol) and methyl chloroformate (130 μL, 1.7 mmol), and the mixture was stirred at room temperature for 48 hours. The mixture was cooled to 0 °C and 25% w/v aqueous ammonia solution (1 mL) was added. After 15 minutes, the aqueous phase was separated and the pH was adjusted to 1 with concentrated HCl. The aqueous phase was extracted with EtOAc (2 x 5 mL). The combined organic fractions were dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (BEH column, C18, 30 x 150 mm) using 10 mM ammonium formate in water (pH 3.8) and MeCN. Fractions were combined and lyophilized. The residue was diluted in 33% HBr in AcOH (2 mL) and the mixture was stirred at 40 °C for 6 h. The reaction mixture was cooled to room temperature and directly lyophilized. Triturate the solid in MeCN (5 mL) and filter the suspension; The mother liquor was discarded. The solid was lyophilized to give the title compound gaboxadol d6 (20 mg, 44% yield over 3 steps) as a solid. MS(ESI) [M+H] ⁺ 147.1.

Analysis of the final product is shown in Table IV below.

Table IV

*Assuming equal sensitivity of MS for each compound.

달튼의 차이가 있었다.The measured mass of the compound C ₆ H ₂ D ₆ N ₂ O ₂ is

Dalton had a difference.

Analysis of the product of this particular synthesis showed 78.4% d6 gaboxadol by HRMS. The presence of gaboxadol, gaboxadol d1 and gaboxadol d2 was not observed; Traces of gaboxadol d3 (0.1%) and gaboxadol d4 (1.7%) were detected by HRMS. The presence of gaboxadol d5 (19.8%) may be due to incomplete deuteration in the first step and/or isotope erosion in the last step through the following scheme:

Potential isotopic erosion can be ameliorated by performing benzyl deprotection using DBr in AcOD. The exact location of H in d5 gaboxadol is currently unknown. Since no non-deuterated gaboxadol was detected, the final composition obtained by the method is at least 98% deuterated gaboxadol, at least 99% deuterated gaboxadol, or possibly 100% deuterated gaboxadol. It can be described as having a copy stone. Also, the final composition obtained by the above method may be described as 78.4% of d6-gaboxadol to specifically indicate the amount of d6-gaboxadol.

!@#

Example 6: Whole-Brain Drug Screening Platform

Currently, many preclinical assays are used to describe or predict the clinical effects of new drugs on the brain. It is an in vitro high-content screening (HCS) assay that measures the pharmacokinetics of a drug on specific molecular target(s) and its effect(s) in simple cellular assays, relatively low resolution (PET/CT, PET/MRI, fMRI ), in vivo assays that measure global responses or local responses with high cellular resolution (electrophysiology or two-photon imaging), and behavioral assays that measure animal behavior in a variety of tasks (Jain and Heutink, 2010; Judenhofer et al., 2008; Markou et al., 2009).

To assess neuronal activity in areas less accessible to live imaging, an early early gene (IEG), such as c-fos, whose expression levels reflect recent changes in neuronal activity, has been used as a proxy. The first in vivo example of neuron-induced c-fos expression was reported in the dorsal horn of the spinal cord after a nociceptive stimulus (Hunt et al., 1987). Since then, upregulation of the expression of IEG, such as c-fos, arc, egr-1, fosb and npas4, has been used as a proxy for neuronal activity in most neuronal systems and most brain regions.

The pharmacomapping approach to preclinical testing of psychiatric drugs is the most direct readout of drug-induced brain activation or inhibition in animals, as psychiatric drugs express their effects through activation or inhibition of specific neural circuits and cell types in the brain. It is based on the suggestion of a relevant preclinical assay.

Importantly, in contrast to the limitations of other methods for measuring brain activation, such as PET/CT, PET/MRI and phMRI, which suffer from low spatial resolution, or electrophysiology or two-photon imaging, which suffer from limited spatial extent, the disclosed The “Pharmacomapping” approach enables direct visualization and measurement of drug-induced brain activation or inhibition across the entire mouse brain with unprecedented single-cell resolution.

This method, referred to as “Pharmacomapping” (implemented by CRO Sertera Inc., Farmingdale, N.Y.), is generally a drug-induced expression of the early-stage gene (IEG) c-fos. Based on an automated drug-screening platform (Renier, et al., (2016); Azevedo, et. al., 2020a; Azevedo, et al., 2020b) that includes whole-brain detection of neuronal activation (Herrera and Robertson 1996) . Prior to pharmacomapping, detection of c-fos as a marker of brain activation can be achieved by in situ hybridization or immunohistochemistry in brain tissue sections, followed by mounting of sections on microscope slides, manual imaging and primarily visual quantification. , required a time-consuming and laborious method. Nonetheless, over the past 20 years, multiple studies have used this method to test drug-induced activity in the brain of mice or rats for a variety of antipsychotic drugs, including antipsychotics, antidepressants, stimulants and anxiolytics (Engber et al., 1998; Kiss, 2018; Salminen et al., 1996; Semba et al., 1996; Slattery et al., 2005; Sumner et al., 2004). These studies represent a validation of the concept of using c-fos expression in the rodent brain in antipsychotic drug screening, although typically only a few brain regions are examined at a time (Sumner, et al., 2004).

In contrast to ready-made methods, pharmacomapping methods are mainly automated and standardized whole-brain immunostaining and brain removal, in combination with advanced microscopy (light-sheet fluorescence microscopy, LSFM), computational (e.g., machine learning) and statistical methods. (FIG. 12 ; see, eg, published US Patent Application No. 2014/0297199, the contents of which are incorporated herein by reference in their entirety). The first generation of these platforms was serial two-photon tomography (STPT) as a method for imaging and c-fos-GFP mice expressing green fluorescent protein (GFP) under the control of the c-fos promoter. (See, eg, published US Patent Application No. 2014/0297199, the contents of which are incorporated herein by reference in their entirety).

The second-generation pharmacomapping platform currently used by Sertera uses a whole-brain immunostaining and clearing procedure, named iDISCO+, and whole-brain imaging by light-sheet fluorescence microscopy, using c-fos in wild-type mice. -Detect positive neurons (Renier et al., 2016). Thus, the pharmacomapping platform uses the well-established concept of c-fos expression as a cellular marker of neuronal activation, and standardized and highly quantitative whole-brain capable of generating detailed and reproducible drug-induced whole-brain activation patterns. Applied as an assay, it is referred to as PHARMACOMAPS®.

Example 7: Mapping the Effect of Deuterated Gaboxadol in Inducing Brain Activation(s) Associated with Achievement of Rapid Relief of Depressive Symptoms

The use of pharmacomapping was previously described with reference to FIG. 12 . To test the activity of deuterated d2-gaboxadol, in a whole-brain pharmacomapping assay, 4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridine-3(2H)- d2-gaboxadol 7,7, on-7,7-d2 (d2-gaboxadol 7,7), was first administered at a human equivalent dose (HED) of a 30 mg dose in the low range of expected clinical efficacy. Phosphorus, tested at a concentration of 6 mg per kg.

A formulation of d2-gaboxadol 7,7 (or vehicle as control) prepared according to Example 1B above was formulated in a pharmaceutically acceptable carrier and administered to 6 mice by intraperitoneal (ip) injection at the indicated dose. was administered to mice of (see Figs. 13-19 ). 2.5 hours after administration, mice were euthanized and brains were immediately embalmed with 4% paraformaldehyde (PFA).

As shown in Figures 13 and 14 , d2-gaboxadol 7,7 at 6 mg/kg surprisingly resulted in significantly higher brain activation than non-deuterated gaboxadol in several brain regions involved in cognitive processing and antidepressant drug activity. caused These areas include areas of the frontal cortex, such as medial orbital cortex (ORBm), hypolimbic cortex (ILA), dorsolateral anterior cingulate cortex (ACAd), association cortical areas such as agranular lateral inferior hypogonal cortex (AI), taste cortex (GU), instinctive cortex (VISC), and foregut (CLA), the rostral part of the lateral septum (LSr) and the anterior part of the stratum nuclear demarcation striatum (BSTa). The magnitude of d2-gaboxadol-induced brain activation in these regions was more comparable for non-deuterated gaboxadol at higher doses of 10 or 20 mg/kg ( FIGS . 13-15 ). These data show a leftward shift in dose response for the d2-gaboxadol form, with d2-gaboxadol requiring lower doses to induce brain activation similar to that of non-deuterated gaboxadol. did Note that the drug dose-response relationship describes the magnitude of the drug-induced response as a function of increasing dose, which can be described by a dose-response curve. Dose response measurements, dose response curves and dose-response model development are pivotal in determining safe dosages for drugs. For example, a leftward shift of a dose-response relationship or curve may mean that a drug that exhibits a leftward shift may elicit a similar desired biological response at lower doses, which translates into a safer drug profile.

Another way of looking at the data is that increasing doses of both deuterated and non-deuterated gaboxadol lead to specific maximal levels of brain activation in many specific regions, which is comparable to the activation induced at higher drug doses. to observe what leads to a decrease in The physiological basis for the reduction in drug-induced brain activation at higher doses in specific regions is not fully understood, but is assumed to be significant for the therapeutic outcome of treatment. For deuterated gaboxadol, maximal brain region activation is achieved at significantly lower doses than for non-deuterated gaboxadol. It also shows a leftward shift in the dose response.

Gaboxadol at doses higher than 20 mg/kg showed a more complex brain activation pattern, with some brain regions such as ORBm, ILA and frontal regions of ACAd cortex being less activated at higher doses, and basal ganglia ( Other brain regions such as the dorsal striatum, also known as CP), are only activated at doses above 20 mg/kg.

To test whether the leftward shift in dose response observed for d2-gaboxadol persists at higher doses, we next tested d2-gaboxadol at 6, 10 and 20, 30 mg/kg. Brain activation evoked by was determined. As shown in Figures 16 and 17 , d2-gaboxadol 6, 10, and in some cases 20 mg/kg doses, in fact in specific brain regions (e.g., ILA and CP), dosing of equivalent doses of non- It induced higher levels of brain activation than those obtained with deuterated gaboxadol, confirming the dose shift response observed with 6 mg/kg of d2-gaboxadol. This is further quantified in FIGS. 18 and 19 .

19 presents the increase in c-fos+ cell numbers in drug-treated mice expressed as percent from control saline-treated mice for selected brain regions as follows: A) Ventral side of the anterior cingulate cingulate (ACAv) segment, B) full length (CLA), and C) basal ganglia (CP). In the left panel the concentration of d2-gaboxadol is provided below the graph, aligned for d2-gaboxadol and gaboxadol. In the right panel, the concentrations of d2-gaboxadol are provided above each graph, the concentrations of gaboxadol are provided below each graph, and the dose curves, d2-gaboxadol 6 mg/kg to gaboxadol align to 10 mg/kg, 10 mg/kg of d2-gaboxadol to 20 mg/kg of gaboxadol, 20 mg/kg of d2-gaboxadol to 30 mg/kg of gaboxadol, Finally, d2-gaboxadol 30 mg/kg was aligned to gaboxadol 40 mg/kg to approximately match the responses.

Example 8: Mapping the effect of d6-gaboxadol in inducing brain activation(s) involved in reducing the risk of suicide and/or achieving rapid relief of depressive symptoms

To test the activity of d6-gaboxadol in a whole-brain pharmacomapping assay, d6-gaboxadol was tested versus non-deuterated gaboxadol at concentrations of 6, 10 and 20 mg/kg. As shown in Figures 20-24 , d6-gaboxadol evokes significantly higher brain activation than non-deuterated gaboxadol at the same dose across multiple brain regions involved in cognitive processing as well as antidepressant drug activity. did

Formulations of d6-gaboxadol (or vehicle as control) were prepared according to Example 5 above, formulated in a pharmaceutically acceptable carrier (0.9% saline), and administered by intraperitoneal (i.p.) injection at the doses indicated. was administered to 6 mice. 2.5 hours after administration, mice were euthanized and brains were immediately embalmed with 4% paraformaldehyde (PFA).

Starting with FIG. 20 , side-by-side images in the top panels, with corresponding histogram quantifications below each panel, are 6 mg per kg (left two panels), 10 mg per kg (middle two panels) and right Two panels show part of the pamacomab pattern induced by d6-gaboxadol and gaboxadol at 20 mg/kg. Taken together, these experiments demonstrate that d6-gaboxadol is used in the periorbital cortex (PERI) and central amygdala (CEA) at 6 mg/kg, in the piriform cortex (PIRI) and stratified nuclear striatum (BST) at 10 mg/kg and at 10 mg/kg. It was found that at 20 mg it induced consistently higher brain activation than gaboxadol, including in the BST and basal ganglia (CP). A comparison of each drug dose between d6-gaboxadol and gaboxadol is further quantified in FIGS. 21-23 . Specifically, d6-Gaboxadol, in addition to the anterior part of the striatum demarcation (BSTa), including the BST rhomboid muscle nucleus (BSTrh) and blue spot (LC), as well as gustatory (GU), instinctive (VISC), agranular Gaboxadol induced higher brain activation than 6 mg/kg of gaboxadol in association cortex including lateral dorsolateral cortex (AI), both dorsal (AId) and posterior (AIp), temporal association (TEa) areas and anterior cingulate (CLA) (FIG. 21 ), while d6-Gaboxadol at 10 mg per kg, in addition to the anterior part of the striatum (BSTa), including the BST rhomboid muscle nucleus (BSTrh), dorsal (ACAd) and ventral (ACAv) anterior cingulate cortex (ACA), sublimbic cortex (ILA), gustatory (GU), instinctive (VISC), agranular lateral dorsolateral cortex (AI) both dorsal (AId) and posterior (AIp), It was more effective than gaboxadol in inducing brain activation in association cortical regions, including the temporal association (TEa) region and the frontal lobe (CLA) ( FIG. 22 ), and finally, d6-gaboxadol at 20 mg/kg was effective in BST Contains the anterior part of the striatum (BSTa), the BST trigeminal sensory nucleus (BSTpr), the BST interstitial nucleus (BSTif), and the BST transverse nucleus (BSTtr), including the nucleus accumbens (BSTrh), the lamina nucleus (BSTov). Higher brain activation than gaboxadol in the posterior part of the lower layer nuclear demarcation striatum (BSTp), the ventral striatum (STRv) including the posterior tubercle (OT) and the nucleus accumbens (ACB), and the auditory fossa (LC) and basal ganglia (CP). induced (FIG. 23 ). Taken together, these data suggest that d6-gaboxadol is present in many cortical brain regions associated with cognitive processing that may affect depression, and in subcortical brain regions associated with emotional and motivational processing that also likely influence depression. , showing higher potency than gaboxadol in inducing brain activation across the three tested doses.

In a further set of experiments, as a proxy for the time point when different forms of gaboxadol reach the animal's brain and elicit these behavioral effects - video recordings in the open field test (OFT) while animals are shown to become immobile. For the purpose of utilizing reduced-sedation, the onset of sedation in mice was compared among d6-gaboxadol, d2-gaboxadol 7,7 and non-deuterated gaboxadol. As shown in Figure 24 , the d6-gaboxadol-induced onset of sedation at 11 minutes (reflected by the onset of immobility) was faster than that of d2-gaboxadol 7,7 at 13 minutes, while d6 The onset of sedation of both -gaboxadol- and d2-gaboxadol 7,7-induced was earlier than that of gaboxadol at 15 minutes. These data suggest that the d6-gaboxadol-induced effect has a much faster onset than that of d2-gaboxadol 7,7, suggesting that the deuterated form of gaboxadol is more likely to induce brain activation in pharmacomapping experiments. Besides high potency, they have been found to have a faster onset of their effect in the brain.

Example 9: Mapping Brain Activations Underlying the Action of Ketamine as a Short-Acting Antidepressant

Traditional antidepressants, when applied acutely in single doses selected to match the human equivalent doses used in the clinical treatment of depression, affect the frontal cortex, striatum nucleus striatum (BST), central amygdala (CEA), paraventricular nucleus hypothalamus. (PVH), paraventricular nucleus thalamic nucleus (PVT), and auditory fossa (LC), evoking discreet patterns of brain activation (Slattery et al., 2005; Sumner et al., 2004). Intravenous ketamine, used acutely in subanesthetic doses, has been shown to act as a very rapid and potent antidepressant with a positive therapeutic effect within a few hours instead of the typical 2 to 3 weeks required for the therapeutic effect of traditional antidepressants (Artigas, 2015 ; Greden, 2002). Although this clinical efficacy of ketamine has been reproduced in multiple clinical studies, the mechanisms by which ketamine achieves these effects remain largely conjecture.

Using a pharmacomapping platform, the whole-brain effects of acute single-dose ketamine were screened at three doses: 1) 5 mg/kg (human equivalent dose, HED 25 mg), which acts as a rapid antidepressant is less than the subanesthetic dose shown to be; 2) 10 mg/kg (HED 50 mg), which is comparable to clinical rapid antidepressant doses; 3) 100 mg/kg, which is an anesthetic dose not known to have any antidepressant properties (Galvez et al., 2018; Lapidus et al., 2014; Lowe et al., 2020). These experiments showed that, while weak activation at 5 and 100 mg/kg, only at the 10 mg/kg dose there was a striking effect involving very strong and widespread activation involving many cortical areas and central hypothalamic nuclei as well as several other brain structures. A bell shaped dose-response curve was found (FIG. 25 ). This pattern is not only very strong, but it is believed to be inconsistent with any other pattern from FDA-approved drugs screened by pharmacomapping to date.

Starting from the rostral part of the brain at 1.5 mm of bregma, 10 mg/kg of ketamine (but not 5 or 100 mg/kg) was administered in the anterior cingulate (ACA), prelimbic (PL) and lower limbic system. (ILA) as well as the cutaneous cortex (PIR) and the nucleus accumbens (ACB) of the ventral striatum (Fig . 25 ). Moving caudally, the ACA and PIR continue to show significant activation by 10 mg/kg ketamine, and are present in associational instinct (VISC), gustatory (GU), and agranular lateral temporal cortex (AIp) cortical regions. A similar activation is observed for The lateral septum (LS) and the anterior part of the striatum nucleus accumbens (BSTa) are also activated. At the bregma level - 1.8 mm, cortical regions include the occipital lobe (RSP), motor (MO), vocal (SS), auditory (AUD), temporal association (TEa), peri-olfactory (PERI) and entorhinal cortices, At 10 mg/kg, it continues to show a very broad activation pattern selectively. Also activated were the paraventricular nucleus (PVT), dorsomedial hepatic nucleus (IMB), medial central nucleus (CM), and rhomboid nucleus (RH), as well as central thalamic nuclei, including the cortical amygdala and central amygdala (CEA). Very broad cortical activation continues caudally further to the visual (VIS), external olfactory (ECT) TEa, AUD, PERI, and ENT cortical regions, as well as the medial geniculate complex (MG) and peraqueductal gray matter (PAG) and noradrenergic (noradrenergic) blue spots (LC) ( FIG. 25 ).

Example 10: Discovery of the unexpected potential of gaboxadol as a rapid antidepressant and anti-suicidal effect

In addition, a ketamine dose of 10 mg/kg, which elicited broad activation in pharmacomapping assays, was found to be a multifactorial response used to model depression such as forced swimming, tail suspension, and learned helplessness. It has been shown by other literature to have an acute positive effect in mouse behavioral studies (Autry et al., 2011; Browne and Lucki, 2013). Importantly, the equivalent HED of 50 mg ketamine per 60 kg person is equivalent to the 0.5 to 1 mg/kg dose used to achieve rapid antidepressant effects and alleviate suicidal ideation in clinically depressed patients, even in treatment-resistant patients. within the human dosage range (Domany et al., 2020; McIntyre et al., 2021; Marcantoni et al., 2020; Zhou et al., 2020; Lowe et al., 2020). Therefore, based on pharmacomapping results, the ketamine-induced activation pattern at 10 mg/kg showed a neuronal circuit-based mechanism of action for the rapid and dramatic therapeutic effects of ketamine on clinically observed depression and suicidal ideation. predicted to be Based on this assumption, the present application will predict that other compounds that induce similar pharmacomab in the assay of the present application should also act as rapid antidepressants in the clinic.

These findings demonstrated that non-deuterated gaboxadol at a dose of 10 mg/kg induced brain activation very similar to that of ketamine, providing the first evidence that gaboxadol may indeed act as a rapid antidepressant and anti-suicide agent. to provide. As shown in Figure 26 , broad cortical activation and to a lesser extent central line thalamic activation and activation of midbrain PAGs and brainstem LCs are very similar between gaboxadol and ketamine, which is comparable to HED 50 mg (60 kg human). It suggests that gaboxadol may have the same therapeutic efficacy as ketamine in treating depression and suicidal ideation.

What is additionally surprising and worth noting about these findings is that gaboxadol and ketamine are structurally unrelated molecules and act through two completely different molecular targets: ketamine is an important part of excitatory synaptic transmission in the brain, NMDA. While an antagonist of type glutamatergic receptors, gaboxadol is an agonist in subunits containing GABAergic receptors, which are an important part of inhibitory synaptic transmission in the brain. Thus, the finding that gaboxadol causes brain-wide activation consistent with the pattern of ketamine is wholly unexpected and cannot be predicted based on previous scientific literature or knowledge. The unexpected nature of such a finding is that gaboxadol was tested almost as a hypnotic agent by Lundbeck with the expectation that it would inhibit brain excitation by acting through the target inhibitory GABA receptor, despite failing for this indication in clinical trials. It is clear from the fact that it has been Similarly, gaboxadol has been tested for its ability to suppress abnormally increased brain excitability in two developmental disorders, Angelman syndrome and fragile X syndrome (ClinicalTrials.gov identifiers: NCT03697161 and NCT04106557). Thus, the believed inhibitory action of gaboxadol is in direct opposition to the current findings of gaboxadol-induced extensive brain excitation.

Example 11: Synergistic effect of gaboxadol and ketamine

Based on this hypothesis of a shared downstream circuit, the data show that 10 mg/kg of non-deuterated gaboxadol and 10 mg/kg of ketamine elicit similar brain activation patterns. As mentioned above, since gaboxadol and ketamine act through very different molecular targets, the GABA _A receptor and the NMDA receptor, respectively, one might expect them to initially involve different signaling events. At the same time, the similarity of the evoked activation patterns suggests that early compound-specific signaling events lead to normal downstream brain circuit activation.

We next tested whether non-deuterated gaboxadol and ketamine could indeed synergize their brain activating effects. As shown in Figure 27A , gaboxadol at 3 mg/kg or ketamine at 6 mg/kg alone did not induce any detectable brain activation using this assay. However, the combination of 3 mg/kg gaboxadol and 6 mg/kg ketamine induced clear activation of multiple cortical regions; These regions were also individually activated by each drug when administered at a total dose of 10 mg/kg as described above. Synergistic effects were also observed with the combination of 5 mg/kg of non-deuterated gaboxadol and 5 mg/kg of ketamine, as shown in Figure 27B . These data show that non-deuterated gaboxadol and ketamine can synergize in their brain activating action, suggesting that combination therapy at each subthreshold dose (synergistic dose) is effective against each of the drugs. This suggests an effective strategy to achieve the desired rapid onset therapeutic effect while avoiding specific possible side effects.

Example 12: Effects of gaboxadol and ketamine in the forced swimming task

The forced swim test is a frequently used behavioral protocol with well-established therapeutic predictability for a wide range of antidepressants, including ketamine (Porsolt et al. 1977; Cryan and Mombereau 2004; Cryan et al. 2005; Lucki et al. 2001 ). In this test, mice are placed in a beaker filled with water, struggle, swim, and float time is measured, which measures float time - when the mouse stops struggling to swim - as a behavioral correlate of depression. use as

To test whether non-deuterated gaboxadol exhibits the same behavioral effects as ketamine, a single dose of ketamine (10 mg/kg) or non-deuterated gaboxadol on forced swimming behavior at 1 h and 24 h after drug delivery The effect of gaboxadol (10 mg/kg) was compared. As shown in FIG. 28 , other groups showing that this dose of ketamine significantly reduced the time drug-treated mice spent floating at both the 1 hour and 24 hour time points compared to the vehicle treated control group. Previous results have been reproduced (Autry et al., 2011; Browne and Lucki, 2013). Surprisingly, the group of mice treated with gaboxadol showed almost identical behavioral effects to the ketamine group ( FIG. 28 ). This is pharmacomab brain activation data shown in FIG . 26 that gaboxadol (10 mg/kg) acts in a similar way to ketamine (10 mg/kg) and is likely to exhibit similar efficacy against treatment-resistant depression and suicidal ideation. supports the conclusion of The data in Figures 13-19 as well as 20-24 further support that deuterated gaboxadol exhibit higher efficacy at lower doses than non-deuterated gaboxadol.

In summary, the data demonstrate that 1) ketamine (10 mg/kg) acts in a completely novel way as an antidepressant that elicits very extensive cortical and central thalamic activation in contrast to traditional antidepressants that elicit much more limited brain activation; 2) Gaboxadol (10 mg/kg) evokes an activation pattern very similar to ketamine, despite having no structural similarity and acting through different molecular targets; 3) Gaboxadol and ketamine act synergistically in their brain activating effects; 4) According to the brain activation data, it is demonstrated that gaboxadol showed almost the same effect in the forced swimming test. Thus, based on these data, gaboxadol may have similar efficacy to ketamine in treating psychiatric disorders such as depression and suicidal ideation. Additionally, in certain instances, deuterated gaboxadol exhibits higher levels of brain activation in certain brain regions than levels of brain activation provided by lower doses of non-deuterated gaboxadol.

Other rodent behavioral models are commonly used to test neuropsychiatric modulators and can be used to demonstrate the effects of compounds on animals. Wang et al (2017) Progress in Neuro-Psychopharmacology and Biological Psychiatry Volume 77, 3 July 2017, Pages 99-109 https://doi.org/10.1016/j.pnpbp.2017.04.008; and [by Krishnan and Nestler "animals of Depression: Molecular Perspectives" (in J.J. Hagan (ed.), Molecular and Functional Models in Neuropsychiatry, Current Topics in Behavioral Neurosciences 7, DOI 10.1007/7854_2010_108 ©Springer-Verlag Berlin Heidelberg 2011, published online 12 January 2011) are incorporated herein by reference in their entirety.

Example 13: Orally disintegrating film of deuterated gaboxadol

The hydrophilic film former was obtained from a graft copolymer having a polyethylene glycol (PEG) plasticizer and a film forming block of polyvinyl alcohol (PVA) Kollicoat IR® (available from BASF) having a molecular weight of about 45,000 Da. manufacture The gelling agent is Gelcarin 379 (commercially available from FMC Biopolymer), a compound of the carrageenan family. Introduce Kollicoat IR® to 70% of the purified water volume while stirring. Stirring is maintained until the Kollicoat IR® is dissolved. Since bubbles are generated, the solution can be dissolved under vacuum or the solution can stagnate until the gases are dispersed (very low viscosity). Tween 80 is incorporated into the stirred solution and flavoring (condensed licorice extract and peppermint essential oil) and sweetener (acesulfame potassium) are added. Stirring is continued until all powder is completely dissolved. Deuterated gaboxadol is introduced with stirring until dispersed in the mixture, then the remaining water (30%) is added. Gelcarin 379® is incorporated into the suspension with stirring to prevent agglomerate formation. The final mixture was deuterated gaboxadol 6% w/w, Kollicoat IR® 15% w/w, Gelcarin 379® 5% w/w, Tween80 0.2% w/w, acesulfame potassium 0.05% w/w. It is composed of w, fragrance 1.5% w/w, and an appropriate amount (qs.) of purified water. Mixed aliquots are then coated on a polyester backing and dried in a type Lab Dryer Coater (Mathis equipment). The coating surface is cut into 6 cm ² units using a manual press and then manually packaged in a sealed bag.

Example 14: Prospective evaluation of the efficacy of deuterated gaboxadol in patients at risk of suicide.

This study was designed to determine whether deuterated gaboxadol would lead to an improvement in one or more symptoms of suicide risk, such as suicidal ideation. As assessed by the Scale for Suicidal Ideation (SSI) (Beck AT, Kovacs M, Weissman A: Assessment of suicidal intention: the Scale for Suicide Ideation. J Consult Clin Psychol 1979; 47:343-352) scores, clinical A randomized clinical trial of oral deuterated gaboxadol compared to intranasal ketamine hydrochloride was conducted in patients with major depressive disorder with significantly significant suicidal ideation. The primary outcome measure is the SSI score 24 hours post dosing. Other outcome measures include overall depression assessment, clinical assessment and safety measures during the 6-week open-label follow-up treatment. This study lacks the dissociative effects of ketamine but will test whether deuterated gaboxadol compared to ketamine can result in an equal or greater reduction in suicidal ideation at 24 hours. This test was adapted from Murrough et al. (2015) and Grunebaum et al (2017), (Grunebaum et al., 2018).

method

a) participant

Eligible patients are 18-65 years of age, with a DSM-IV diagnosis of major depressive disorder, a score >16 on the 17-item Hamilton Depression Rating Scale (HAM-D) (Hamilton, 1960), and a clinically significant cutoff for suicidal ideation. have a score >4 on the considered SSI (Brown et al., 2000; Holi et al., 2005; Price et al., 2014). A prospective study of 6,891 psychiatric outpatients (Brown et al., 2000) found that a baseline SSI score >2 predicted suicide, adjusting for other risk factors, during follow-up of up to 20 years. Eligible patients are voluntarily admitted to the inpatient laboratory and discharged when the patient is assessed to be stable and not an imminent safety risk. Exclusion criteria were: unstable medical or neurological illness, significant ECG abnormalities, pregnancy or lactation, current psychosis, history of gaboxadol or ketamine abuse or dependence, other drug or alcohol dependence within the past 6 months, binge eating substance use or withdrawal. suicidal ideation due to suicidal ideation, previous futile trials or adverse reactions to gaboxadol or ketamine, daily opioid use >20 mg oxycodone or equivalent for 3 days prior to infusion, brief mental status examination in persons <60 years of age score <25, lack of ability to consent, and insufficient understanding of English. There were no exclusions for body mass index or body weight. Participants are allowed to continue on their current stable psychiatric medication, except that they do not take a benzodiazepine within 24 hours prior to infusion. Recruitment is done through Internet and local media advertisements and clinician referrals. The protocol was approved by the Institutional Review Board and written informed consent was obtained from all participants.

b) intervention

In a dose range study, deuterated gaboxadol hydrochloride, for example, as an oral capsule, at 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, or 100 mg per day, or Participants are randomized to receive daily ketamine at 0.5 mg/kg in 100 mL normal saline infused over 40 minutes. Blood pressure, heart rate and respiratory rate are monitored every 5 minutes. A psychiatrist or psychiatric nurse qualified in advanced cardiac resuscitation conducts treatment, and an anesthesiologist is available for consultation over the phone.

A baseline EEG or MEG can be established within 30 minutes prior to patient treatment. The EEG or MEG may be continued throughout treatment or may be re-evaluated at specific time points such as 30, 45, 60, 90, 120, 150 or 160 minutes after administration.

If the patient's examination undoubtedly reveals an insufficient response to deuterated gaboxadol treatment observed during the first 160 minutes post-administration, the treating physician may optionally administer a second dose of deuterated gaboxadol. there is. An inadequate response can be defined as an increase in EEG power density of less than 30% at 160 minutes after the first administration. Preferably, the EEG power density is calculated in the range of 4.75-8.0 Hz.

Alternatively, an insufficient response is an increase in whole-head MEG planar durometer less than +3 in combined delta, theta and alpha activity at 160 minutes after first administration. The second administration of deuterated gaboxadol is given within about 12 hours of the first administration. An inadequate response may also include observable clinical symptoms indicating a lack of response.

After the 24-hour assessment, participants receive optimized standard clinical pharmacological treatment for 6 months, with weekly study assessments for the first 6 weeks at uncontrolled follow-up.

c) results and measurements

The evaluator is a doctoral or master's level psychologist. A diagnosis involving substance abuse or dependence was made using the Structured Clinical Interview for DSM-IV Axis I and II Disorders (SCID I and II) (First et al., 1995a,b) at weekly consensus meetings of the research psychologist and psychiatrist. Clinical Interview) is used. Suicidal ideation due to binge eating substance abuse is assessed by clinical history, past antidepressant trials and current medications are cataloged in the baseline clinical-demographic form of this application, which examines a variety of variables not captured by other instruments. Video-recorded assessments are used for weekly reliability monitoring. The intraclass correlation coefficients for the major clinical assessments were 0.94 for SCID I, 0.96 for HAM-D and 0.98 for SSI. The clinician-rated SSI rated the current severity of suicidal ideation as a 19-item scaled from 0 (least severe) to 2 (most severe) (Beck et al., 1979). The items examine wish to die, passive and active suicidal ideation, duration and frequency of thoughts, sense of control, inhibition, and preparatory behavior for attempt (Brown et al., 2000). The SSI has moderately high internal consistency and good simultaneous and discriminant validity. At screening, administer within 24 hours before infusion at baseline, 230 minutes after infusion, 24 hours after infusion and follow-up at Weeks 1-6. For brevity, this application uses “Day 1” to refer to the 24-hour treatment assessment. Depressive symptoms were assessed with the 17- and 24-item HAM-D (Hamilton, 1960), the Beck's Depressive Inventory (BDI) (Beck et al, 1961), and the Mood State Profile (POMS) (McNair et al., 1992). do. Anxiety is measured on a 5-point Likert scale that asks patients to rate themselves on a scale of 0 (not at all) to 4 (extremely anxious). Adverse events were assessed using the Systematic Assessment-General Survey for Emergency Care Cases (Levine and Schooler, 1986), the Clinician-Administered Dissociative State Scale (CADSS; score range, 0-92) (Bremner et al., 1998), and conceptual It is measured by the Positive Symptom Subscale (subscale score range, 0-24) of the Brief Mental State Rating Scale (BPRS), including confusion, grandiose confidence, hallucinations and delusions (Overall and Gorham, 1962). Efficacy assessments and CADSS and BPRS positive symptom subscales (baseline, 230 minutes and day 1) are collected by a psychologist rater who was not present during treatment. Administration of CADSS and BPRS positive symptom subscales and assessment of all adverse events after immediate treatment is performed by the physician supervising the infusion. Participants are asked at 3 and 6 months post-study about use of deuterated gaboxadol.

d) randomization and blinding

A permuted blocked design is used with block size randomized between 4 and 6 with equal probability and 1:1 allocation between treatments. Randomization is stratified for two baseline factors: whether the patient is taking psychiatric medications (yes/no) and whether the patient's baseline SSI score is <8 or >8. The latter stratification factor, based on median baseline SSI scores from a previous clinical trial in patients with suicidal depression (Grunebaum et al., 2012), increases the likelihood that treatment groups will be similar in baseline SSI severity. Patients and study personnel were blinded to treatment. To assess the adequacy of blinding, at the Day 1 assessment, patients and raters are asked if they think the infusion is ketamine or deuterated gaboxadol, or "don't guess".

Treatment response is defined as a Day 1 SSI score >50% below baseline. This application defines remission more stringently as a Day 1 SSI score >50% below baseline and less than an eligibility threshold of 4. The level of remission of improvement is defined to ensure that the ketamine group has every opportunity to receive deuterated gaboxadol. Non-remitters are unblinded, and those receiving ketamine are given an open-air deuterated gaboxadol infusion, usually the next day. Existing medications will remain constant from the pre-infusion baseline until the completion of the Day 1 assessment after the final infusion. Responders remain blinded and receive a letter from the pharmacy informing them of the randomized drug after completing follow-up treatment.

e) statistical analysis

We reinforce this study by assuming a two-sided test of group effects at an alpha level of 0.05. Effect size estimates, standard deviations and correlations are based on previous reports (Grunebaum et al., 2012) (Price et al., 2009). A planned sample size of 70, assigned 1:1 to each treatment, provides >80% power to detect a 25% reduction in SSI score over 24 hours in the none and deuterated gaboxadol groups in the ketamine group do. The actual sample size is about 80. Histograms and residual plots of the results are checked for normality. Group comparisons for baseline characteristics are completed using chi-square tests or Fisher's exact tests appropriate for categorical variables and two-sample t tests for continuous variables. . A modified intent-to-treat analysis included all randomized participants assessed for the primary outcome measure, the Day 1 SSI score (N=80). The primary hypothesis was tested using an analysis of covariance (ANCOVA) model of change in SSI score from baseline to Day 1, with treatment group and baseline SSI score as predictors. The randomization strata (with or without psychiatric medications), which by definition are not related to treatment group, are not included in the model as they are not relevant to the primary outcome measure (p=0.84).

Effect size calculations used Cohen's d and number required for treatment. Cohen's d is calculated by dividing the difference in mean group change by the standard deviation of baseline values for the entire sample. Secondary analyzes used the ANCOVA model to determine differences between groups in SSI scores and depressive symptom assessments (17 and 24 items HAM-D, BDI and POMS) from baseline to 230 minutes, and depressive symptom assessments from baseline to Day 1. Test for enemy changes.

Responses are compared drug by drug using logistic regression. Linear regression is used for exploratory analyzes of treatment effects on the SSI's suicidal desires/ideas and plans subscales (Witte et al., 2006). Intervention analysis is performed using the structural equation modeling framework of Mplus version 7 (Muthen and Muthen, 1998). An unpaired t-test is used to determine whether participants (N=35) assigned to ketamine who received open-label deuterated gaboxadol treatment after Day 1 experience significant subsequent changes in SSI or HAM-D scores. For longitudinal data analysis, mixed effects of 17-item HAM-D score and SSI during the 6-week follow-up period, as 35 of 40 patients in the ketamine group were non-responders and received a subsequent open deuterated gaboxadol infusion. Linear regression is used to test for significant change from baseline across the entire sample, regardless of treatment group. Safety analysis included univariate tests comparing infusion-related cardiorespiratory effects, adverse events, post-infusion severity of benign, dissociative and anxiety symptom assessments between groups. SAS, version 9.4 (SAS Institute, Cary, NC) and SPSS, version 23 (IBM, Armonk, NY) are used for analysis.

e) result

Primary Outcome Measures: Day 1 Mean SSI score in the deuterated gaboxadol group compared to the ketamine group. Calculate Cohen's d for the difference in mean group change to determine whether it represents an effect size above the median. A baseline Borderline Personality Disorder diagnosis was included as a covariate to determine whether it had a negligible effect on outcome.

g) secondary outcome measures

suicidal ideation. Determine whether the proportion of responders to SSI on day 1 is significantly higher in the deuterated gaboxadol group than in the ketamine group. To determine whether there is a greater reduction in suicidal ideation at 230 minutes post-injection in the deuterated gaboxadol group compared to the ketamine group.

depressive symptoms. To determine whether the Day 1 POMS Total Mood Disorder score and/or Depression subscale score show greater improvement in the deuterated gaboxadol group compared to the ketamine group.

Example 15: Mapping Brain Activations Underlying Therapeutic Actions of Lithium in Psychiatry

To understand the mechanism of action of lithium across the entire brain, using the pharmacomapping technique described above, the following mouse doses (equivalent to human equivalent doses (mg): 600, 750, 1000 and 1500) mg/kg): 120, 150, 200, and 300 were mapped for lithium-induced brain activation. These experiments revealed dose-dependent increases in brain activation patterns, including weak to moderate activation of several brain regions at 120 and 150 mg/kg and significantly more extensive activation at 200 and 300 mg/kg ( FIG. 29 ). Activation patterns observed with lithium doses of 120 and 150 mg/kg included the anterior portion of the striatum demarcation (BSTa), central amygdala (CEA), and the lobe (LC) ( FIG. 29 , top two rows). ). The same areas are prelimbic (PL) and hypolimbic (ILA) cortices at bregma 1.5 mm, cucurbital cortex (PIR) and nucleus accumbens (ACB), taste (GU), agranular lateral lobe (AIp) cortical areas, Motor (MO), vocal (SS), auditory (AUD), temporal association (TEa), peri-olfactory (PERI) and enolar cortices, as well as paraventricular nucleus (PVT), dorso-medial, in bregma 0.15 to -1.8 mm Central thalamic nuclei, including the hepatic nucleus (IMB), medial central nucleus (CM), and rhomboid nucleus (RH), and visual (VIS), external olfactory (ECT) TEa, AUD, PERI, and ENT cortical regions, as well as bregma 2.7 In addition to activation of the medial geniculate complex (MG) cortical amygdala in mm, it was significantly activated by 200 and 300 mg/kg of lithium ( FIG. 29 , bottom two rows).

Example 16: Lithium-derived c-fos The pattern of activation is GABA _A It closely matches the pattern of the agonist Gaboxadol.

Mapping the effects of lithium across the mouse brain using the pharmacomapping platform described above allows direct comparison of lithium-induced brain activation patterns to those of other test compounds. Surprisingly, the pattern of pharmacomab evoked by the dose of 300 mg/kg lithium closely matched that of gaboxadol at 20 mg/kg, indicating that 1) motor (MO), gustatory (GU), and visceral (VISC) , agranular lateral dorsal cortex (AI), auditory (SS), auditory, visual (VIS), auditory (AUD), prelimbic (PL) and lower part of the limbic system (ILA), occipital lobe (RSP), body wall (PTL), Wide cortical activation including temporal association (TEa), external olfactory (ECT), internal olfactory (ENT), periolfactory (PERI), cutaneous (PIR), and anterior cingulate (ACA) cortices, as well as the anterior cingulate (CLA) 2) Hippocampal CA1 area, stratum nuclear demarcation striatum (BST), central amygdala (CEA), cortical amygdala (COA), basolateral and basolateral amygdala (BLA and BMA), medial amygdala (MEA), thalamic ventral posteromedial nucleus (VPM) ), subparascapular nucleus (SPF), medial geniculate complex (MG), anterior geniculate nucleus (SGN), nucleus of recombination (RE), rhomboid nucleus (RH), and medial central nucleus (CM) of the thalamus, paraventricular nucleus hypothalamic nucleus (PVH), posteromedial nucleus of the hypothalamus (DMH), mammary nucleus (TM), parathalamic nucleus (PSTN) and hypothalamic nucleus (STN), brachial nucleus, lumbar nucleus (LC), and c-fos activation of subcortical activation involving the nucleus (NTS) to the solitary tract (FIG. 30 ).

This finding is all the more surprising because gaboxadol and lithium are structurally unrelated molecules with different mechanisms of action: gaboxadol inhibits GABAergic receptors, which are thought to constitute the extrasynaptic population of inhibitory GABA _A receptors in the brain. While being an agonist in the delta-subunit that contains, the mechanism of action of lithium in the brain has been shown in several studies to be involved in the inhibitory signaling cascade downstream of glycogen synthase kinase 3-beta, resulting in neurotrophic effects and enhanced neuroplasticity and cellular It has been suggested to lead to cellular resilience, but remains poorly established (Won and Kim, 2017). Thus, the finding that lithium causes brain-wide activation consistent with the pattern seen in gaboxadol is entirely unexpected and could not be predicted based on reports in the scientific literature.

Example 17: Synergy between lithium and gaboxadol in pharmacomapping assay

The similarity of lithium and non-deuterated gaboxadol pharmacomab suggested that early compound-specific signaling events lead to common downstream brain circuit activation. This Example tested whether non-deuterated gaboxadol and lithium could act synergistically with each other, with two doses of each compound under conditions where doses of each compound did not cause any acute brain activation by themselves. Doses were combined. As shown in FIG. 31 , 3 mg/kg of gaboxadol or 85 mg/kg of lithium alone did not induce any brain activation in mice detectable using a pharmacomapping assay ( FIG. 31 , top 2 heat). However, the combination of 3 mg/kg of gaboxadol and 85 mg/kg of lithium induced potent activation of multiple mouse brain regions ( FIG. 31 , bottom row), demonstrating a synergistic effect; These regions were individually activated by each drug when administered at higher doses of 20 mg/kg (gaboxadol) and 300 mg/kg (lithium) as described in Example 16 above.

Furthermore, this synergism is not limited to the lowest doses of lithium (<100 mg/kg) and gaboxadol (<5 mg/kg), but a combination of the two compounds at higher doses, such as gaboxadol 6 It was also observed with the combination of mg/kg and lithium 150 mg/kg (FIG. 32A ) or gaboxadol 6 mg/kg and lithium 200 mg/kg (FIG. 32B ). At higher drug combinations, in addition to synergism, an additive effect between gaboxadol and lithium is also observed. Taken together, these data clearly demonstrate that lithium and gaboxadol can synergize in brain activation, suggesting that combination therapy is an effective strategy to achieve lithium efficacy while reducing lithium-induced side effects. It is also important to note that gaboxadol has been tested in clinical trials and found to have no significant adverse side effects at human doses equivalent to the 6 mg/kg mouse dose used in the current study. For example, in the early 1980s gaboxadol was the subject of a series of pilot studies testing its efficacy as an analgesic and anxiolytic, as well as treatment for tardive dyskinesia, Huntington's disease, Alzheimer's disease and spasticity (Foster et al., 1983; Hoehn-Saric, 1983; Kasper et al., 2012; Kjaer and Nielsen, 1983; Korsgaard et al., 1982; Mohr et al., 1986; Mondrup and Pedersen, 1983). In the 1990s, gaboxadol entered late development for the treatment of insomnia, but development was discontinued after a 3-month efficacy study showed that the compound did not show significant effects on sleep initiation and sleep maintenance (ClinicalTrials.gov identifier: NCT00209963). .

Example 18: Lithium and Gaboxadol Synergism in Amphetamine-Induced Rodent Model of Mania

The stimulant d-amphetamine-induced hyperactivity has been used as a therapeutic predictive rodent test of mania, as pretreatment with lithium has been shown to inhibit amphetamine-induced hyperkinesis (Berggren et al., 1978; Cappeliez and Moore, 1990; Kato et al., 2007). The brain activation synergism between lithium and gaboxadol observed in pharmacomapping experiments should lead to improved inhibition of hyperkinesis than seen with either molecule alone, as both molecules also synergize in the d-amphetamine test suggests

As shown in FIG . 33 , pretreatment with a substandard dose (14.1 mg/kg) of lithium had no behavioral effect, but administration of less than 14.1 mg/kg of lithium in combination with 3 mg/kg gaboxadol was effective. Pretreatment with doses was more effective in suppressing amphetamine-induced hypermobility than either lithium or gaboxadol alone.

Example 19: Mapping synergy between D2-gaboxadol and lithium in inducing brain activation

The results presented in this example demonstrate that the combination of d2-gaboxadol 7,7 and lithium induce synergistic brain activation compared to each compound acting alone. Pharmacomapping was performed on 6 mice per experiment. Images shown represent the average of 6 mice.

To test whether cyclic carbon deuterated gaboxadol synergistically combines with lithium, the present application presents d2-gaboxadol 7,7 6 mg/kg, lithium 150 mg/kg and d2-gaboxadol 7, Brain activation induced by the combination of 7 6 mg/kg and lithium 150 mg/kg was compared. As shown in FIGS. 34 to 38 , these experiments actually showed the nucleus accumbens (ACB) (FIG. 34 ), the anterior portion of the stratum nuclear demarcation striatum (BSTa) (FIG. 35 ), and the ventral tegmental area (VTA) (FIG. 36 ). and LC (Fig. 37 ), revealing synergistic activation between the two compounds across multiple brain regions. Brain activation by the combination of d2-gaboxadol 7,7 and lithium in these regions was significantly higher than the sum of the brain activation effects induced by each compound alone, indicating that d2-gaboxadol 7,7 and lithium synergy between the two was demonstrated (Fig . 38 ).

Referring to FIG. 34 , white is A) d2-gaboxadol 7,7 6 mg/kg, B) lithium 150 mg/kg and C) d2-gaboxadol 7,7 6 mg/kg and lithium 150 mg/kg Shows the spatial area of significant drug-induced activation for the combination in kg. The region of the nucleus accumbens (ACB) is highlighted with a dotted line. The combination of d2-gaboxadol 7,7 6 mg/kg and lithium 150 mg/kg appears to cause synergistic activation of ACB compared to each compound alone.

In FIG. 35 , white indicates a combination of A) d2-gaboxadol 7,7 6 mg/kg, B) lithium 150 mg/kg and C) d2-gaboxadol 7,7 6 mg/kg and lithium 150 mg/kg represents the spatial region of significant drug-induced activation for . The region of the anterior part (BSTa) of the striatum nuclear demarcation line is highlighted with a dotted line. The combination of d2-gaboxadol 7,7 6 mg/kg and lithium 150 mg/kg appears to cause synergistic activation of BTa compared to each compound alone.

In FIG. 36 , white indicates the combination of A) d2-gaboxadol 7,7 6 mg/kg, B) lithium 150 mg/kg and C) gaboxadol 7,7 6 mg/kg and lithium 150 mg/kg represents a spatial region of significant drug-induced activation. The area of the ventral tegmental area (VTA) is highlighted with a dotted line. The combination of d2-gaboxadol 7,7 6 mg/kg and lithium 150 mg/kg appears to cause synergistic activation of ACB compared to each compound alone.

In FIG. 37 , white represents the combination of A) d2-gaboxadol 7,7 6 mg/kg, B) lithium 150 mg/kg and C) gaboxadol 7,7 6 mg/kg and lithium 150 mg/kg represents a spatial region of significant drug-induced activation. The region of the blue half LC is highlighted with a dotted line. The combination of d2-gaboxadol 7,7 6 mg/kg and lithium 150 mg/kg appears to cause synergistic activation of ACB compared to each compound alone.

Figure 38 quantifies the comparison illustrated in Figures 34-37 . Increases in the number of c-fos+ cells in drug-treated mice were found in (A) the nucleus accumbens (ACB), (B) the anterior segment of the striatum of the laminar nuclear demarcation (BSTa), (C) the ventral tegmental area (VTA), and (D) the aqueduct. For peripheral gray matter (PAG), each group: d2-gaboxadol 7,7 6 mg/kg, lithium 150 mg, d2-gaboxadol 7,7 6 mg/kg and lithium 150 mg, gaboxadol 6 mg/kg, and percentage of control saline-treated mice for gaboxadol 6 mg/kg and lithium 150 mg/kg. The dotted line highlights the 100% control baseline. Each d2-gaboxadol 7,7 + lithium and gaboxadol + lithium combination column includes the calculated additive additive effect (above the dotted line) and the measured additional synergistic effect (above the solid line) as a percentage of the control. .

Thus, d2-gaboxadol 7,7 provides a significantly stronger enhancement of synergy with lithium than is found with non-deuterated gaboxadol. The superior effect of deuterated gaboxadol compared to non-deuterated is also shown in the above examples herein. We anticipate that significantly lower doses of deuterated gaboxadol can be used as effectively as higher doses of non-deuterated gaboxadol, and synergy with lithium may be higher as observed in FIG. 38 .

Various references are made herein, such as patents, patent applications, patent publications, journals, scientific articles, books, articles, web content, and other publications. All such documents are incorporated herein by reference in their entirety for all purposes. Any material, or portions thereof, which are said to be incorporated herein by reference but conflict with any prior definitions, statements or other published material expressly set forth herein, are included only to the extent that no conflict arises between the incorporated material and the material of this disclosure. do. In case of conflict, the present disclosure, as the preferred disclosure, shall prevail and the conflict should be resolved.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. Such equivalents are intended to be included in the scope of the claims.

Although the present invention has been described with a certain degree of particularity, it should be understood that this disclosure is completed by way of example only, and that many changes to the details of construction and arrangement of parts may be resorted to without departing from the spirit and scope of the present invention. do.

Cited references

Claims (47)

A cyclic carbon deuterated gaboxadol compound of Formula I, or a pharmaceutically acceptable salt thereof:

(I)
In the above formula,
R4, R4', R5, R5', R7 and R7' are independently H or D;
At least one of R4, R4', R5, R5', R7 and R7' is D. According to claim 1,
wherein the incorporation percentage of deuterium is at least 1%. According to claim 1,
If none of R4, R4', R5 and R5' is H, then both R7 and R7' are not D. According to claim 1,
A compound wherein when R4, R4', R5 and R5' are all D, at least one of R7 and R7' is D. According to claim 1 or 2,
wherein R4, R4', R5, R5', R7 and R7' are all D. A composition comprising at least one cyclic carbon deuterated gaboxadol compound of Formula I, or a pharmaceutically acceptable salt thereof:

(I)
In the above formula,
R4, R4', R5, R5', R7 and R7' are independently H or D;
At least 1% of the compounds have D in one or more of R4, R4', R5, R5', R7 and R7', optionally at least 1% of the compounds have R4, R4', R5, R5', R7 and R7 ' has a D in all. According to claim 6,
wherein at least 10% of the compounds have D at one or more of R4, R4', R5, R5', R7 and R7'. According to claim 6,
wherein at least 10% of the compounds have D at three or more of R4, R4', R5, R5', R7 and R7'. According to claim 6,
wherein at least 10% of the compounds have D at 5 or more of R4, R4', R5, R5', R7 and R7'. According to claim 6,
wherein at least 70% of the compounds have D at 5 or more of R4, R4', R5, R5', R7 and R7'. According to claim 6,
wherein at least 90% of the compounds have D at 5 or more of R4, R4', R5, R5', R7 and R7'. According to claim 6,
wherein at least 75% of the compounds have D in all of R4, R4', R5, R5', R7 and R7'. According to claim 6,
A composition comprising at least two different compounds of Formula I. A pharmaceutical composition comprising the compound of any one of claims 1 to 13 and a pharmaceutically acceptable carrier. According to claim 14,
A pharmaceutical composition in oral dosage form. According to claim 15,
A tablet, a pharmaceutical composition. According to claim 15,
A pharmaceutical composition wherein the oral dosage form is an orally disintegrating form. According to claim 14,
A pharmaceutical composition comprising from about 1 mg to about 300 mg of a compound. According to claim 14,
A pharmaceutical composition comprising about 50 mg to about 100 mg of a compound. According to claim 14,
A pharmaceutical composition comprising about 50 mg, about 75 mg or about 100 mg of a compound. According to claim 14,
A pharmaceutical composition comprising about 25 mg to about 50 mg of a compound. According to claim 14,
A pharmaceutical composition comprising about 10 mg to about 30 mg of a compound. (a) a compound of any one of claims 1 or 6;
(b) lithium, ketamine, AXS-05 (a fixed combination of dextromethorphan and bupropion), SAGE-217, allopregnanolone, ganaxolone, alphadolone, alpaxolone, hydroxydione, minaxolone, pregna Nolon, Lenolone, AV-101 (L-4-chlorokynurenine), Rapastinel (GLYX-13), MGS0039, LY-341,495, MK-801 (dizosylpine), Ro 25-6981, lislenemdaz (CERC-301, MK-0657), afimostinel (NRX-1074), ranisemin (AZD6765), traxoprodil (CP-101606), (2R,6R)-hydroxynorketamine, deagglomerating agent (INN ) (RG1578, RO4995819), memantine, tiagabine, clozapine and [2-amino-4-(2,4,6-trimethylbenzylamino)-phenyl]-carbamic acid ethyl ester (AA29504) at least one other compound; and
(c) a pharmaceutically acceptable carrier
A pharmaceutical composition comprising a. According to claim 23,
A pharmaceutical composition wherein the at least one other compound is lithium. A pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable salt thereof:

(I)
In the above formula,
R4, R4', R5, R5', R7 and R7' are independently H or D;
R4, R4', R5, R5', R7 and R7' are all D in at least 75% of the compounds. According to claim 25,
wherein at least 95% of the total of all positions R4, R4', R5, R5', R7 and R7' are D. According to claim 25,
A pharmaceutical composition wherein up to about 20% of the compound is d5-gaboxadol. A pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable salt thereof:

(I)
In the above formula,
R4, R4', R5, R5', R7 and R7' are independently H or D;
In at least about 10% of the compounds, at least 3 of positions R4, R4', R5, R5', R7 and R7' are D. According to claim 28,
A pharmaceutical composition wherein at least 3 of positions R4, R4', R5, R5', R7 and R7' are D in at least about 50% of the compounds. According to claim 28,
A pharmaceutical composition wherein at least 3 of positions R4, R4', R5, R5', R7 and R7' are D in at least about 70% of the compounds. According to claim 28,
A pharmaceutical composition wherein at least 3 of positions R4, R4', R5, R5', R7 and R7' are D in at least about 95% of the compounds. (a) treating 3-hydroxypyridine-4-carboxylic acid with deuterium oxide under catalytic hydrogenation conditions to provide 2,3,6-trideuterio-5-hydroxy-pyridine-4-carboxylic acid;
(b) treating 2,3,6-trideuterio-5-hydroxy-pyridine-4-carboxylic acid from step (a) with a methylating agent to obtain methyl 2,3,6-trideuterio-5- providing hydroxy-pyridine-4-carboxylate;
(c) treating the methyl 2,3,6-trideuterio-5-hydroxy-pyridine-4-carboxylate from step (b) with hydroxylamine hydrochloride to obtain 2,3,6-tridew providing terio-5-hydroxy-pyridine-4-carbohydroxamic acid;
(d) treating the 2,3,6-trideuterio-5-hydroxy-pyridine-4-carbohydroxamic acid from step (c) with an activator to obtain 4,5,7-trideuterioisoxa providing zolo[5,4-c]pyridin-3-one;
(e) treating the 4,5,7-trideuterioisooxazolo[5,4-c]pyridin-3-one from step (d) with a bromination agent to obtain 6-benzyl-4,5,7-tri providing deuterio-isoxazolo[5,4-c]pyridin-6-ium-3-ol bromide;
(f) treating the 6-benzyl-4,5,7-trideuterio-isoxazolo[5,4-c]pyridin-6-ium-3-ol bromide from step (e) with a reducing agent; providing 6-benzyl-4,4,5,5,7,7-hexadeuterio-isoxazolo[5,4-c]pyridin-3-ol; and
(g) deprotecting the 6-benzyl-4,4,5,5,7,7-hexadeuterio-isoxazolo[5,4-c]pyridin-3-ol from step (f) above; removing the benzyl group to provide d6-gaboxadol
A method for producing d6-gaboxadol, comprising: 33. The method of claim 32,
(a) 2,3,6-trideuterio- providing 5-hydroxy-pyridine-4-carboxylic acid;
(b) treatment of 2,3,6-trideuterio-5-hydroxy-pyridine-4-carboxylic acid from step (a) with methanol and sulfuric acid at reflux temperature to obtain methyl 2,3,6-tridew providing terio-5-hydroxy-pyridine-4-carboxylate;
(c) treating the methyl 2,3,6-trideuterio-5-hydroxy-pyridine-4-carboxylate from step (b) with hydroxylamine chloride and aqueous sodium hydroxide solution to obtain 2,3,6 -providing trideuterio-5-hydroxy-pyridine-4-carbohydroxamic acid;
(d) treating the 2,3,6-trideuterio-5-hydroxy-pyridine-4-carbohydroxamic acid from step (c) with thionyl chloride to obtain 4,5,7-trideuterio-5-hydroxy-pyridine-4-carbohydroxamic acid providing oisoxazolo[5,4-c]pyridin-3-one;
(e) 4,5,7-trideuterioisoxazolo[5,4-c]pyridin-3-one from step (d) is treated with benzyl bromide to obtain 6-benzyl-4,5,7- providing trideuterio-isoxazolo[5,4-c]pyridin-6-ium-3-ol bromide;
(f) 6-benzyl-4,5,7-trideuterio-isoxazolo[5,4-c]pyridin-6-ium-3-ol bromide from step (e) above is mixed with deuterated ethanol and 6-benzyl-4,4,5,5,7,7-hexadeuterio-isoxazolo[5,4-c] by treatment with sodium deuterated borohydride (NaBD ₄ ) in a mixture of deuterium oxides. providing pyridin-3-ol; and
(g) 6-benzyl-4,4,5,5,7,7-hexadeuterio-isoxazolo[5,4-c]pyridin-3-ol from step (f) above (i) methyl chloroformate in the presence of an inorganic base followed by treatment with hydrobromic acid or (ii) treatment with deuterated hydrobromic acid to give d6-gaboxadol.
To include, the method. A product of the method of claim 32 or claim 33 . Compound 4,5,7-trideuterioisoxazolo[5,4- c ]pyridin-3-one. Use of the pharmaceutical composition of claim 14 for the treatment of psychiatric disorders. Use of a compound of claim 1 in the manufacture of a medicament. Use of a compound of claim 1 in the manufacture of a medicament for use in the treatment of mental disorders. Use of a combination of ring carbon deuterated gaboxadol and lithium, or a pharmaceutically acceptable salt of one or both of these compounds, in the manufacture of a medicament for the treatment of a mental disorder. A pharmaceutical composition comprising a cyclic carbon deuterated gaboxadol of formula (I) or a pharmaceutically acceptable salt thereof, and (b) lithium or a pharmaceutically acceptable salt of lithium:

(I)
In the above formula,
R4, R4', R5, R5', R7 and R7' are independently H or D;
At least one of R4, R4', R5, R5', R7 and R7' is D. 41. The method of claim 40,
A pharmaceutical composition, wherein the cyclic carbon deuterated gaboxadol is present in the pharmaceutical composition in an amount of up to about 2/3 of the dosage of non-deuterated gaboxadol required to achieve an equivalent effect. 41. The method of claim 40,
A pharmaceutical composition wherein lithium is present in the pharmaceutical composition in an amount that is a sub-standard daily dose of lithium. 43. The method of claim 42,
A pharmaceutical composition wherein the substandard dose of lithium, when administered daily to a subject in need thereof, is less than the dose medically recommended for treating a psychiatric disorder including bipolar disorder, depression, treatment-resistant depression, and suicidal tendencies. The method of claim 41 ,
wherein the dosage of cyclic carbon deuterated gaboxadol is less than or equal to about 1/3 of the amount of non-deuterated gaboxadol required to achieve an equivalent effect. 41. The method of claim 40,
The pharmaceutical composition is in the form of a single dosage unit having separate compartments for lithium and cyclic carbon deuterated gaboxadol, or a pharmaceutically acceptable salt of one or both of these compounds. 46. The method of any one of claims 40 to 45,
A pharmaceutical composition wherein the cyclic carbon deuterated gaboxadol is d6-gaboxadol. A kit comprising the pharmaceutical composition of any one of claims 40 to 46.

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